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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Idecabtagene vicleucel



Idecabtagene vicleucel

CAS 2306267-75-2

STN: BLA 125736

An autologous T lymphocyte-enriched cell transduced ex vivo with an anti-BCMA CAR lentiviral vector encoding a chimeric antigen receptor CAR, comprising a CD8 hinge and TM domain, 4-1BB costimulatory domain and CD3ζ signaling domain, targeting human B cell maturation antigen for cancer immunotherapy (Celgene Corp., NJ)

  • Bb2121
NameIdecabtagene vicleucel (USAN);
Abecma (TN)
ProductABECMA (Celgene Corporation)
CAS2306267-75-2
EfficacyAntineoplastic, Anti-BCMA CAR-T cell
  DiseaseMultiple myeloma [DS:H00010]
CommentCellular therapy product

USFDA 2021/4/21 APPROVED

Dendritic cells (DCs) are antigen-presenting cells (APCs) that process antigens and display them to other cells of the immune system. Specifically, dendritic cells are capable of capturing and presenting antigens on their surfaces to activate T cells such as cytotoxic T cells (CTLs). Further, activated dendritic cells are capable of recruiting additional immune cells such as macrophages, eosinophils, natural killer cells, and T cells such as natural killer T cells.

Despite major advances in cancer treatment, cancer remains one of the leading causes of death globally. Hurdles in designing effective therapies include cancer immune evasion, in which cancer cells escape destructive immunity, as well as the toxicity of many conventional cancer treatments such as radiation therapy and chemotherapy, which significantly impacts a patient’s ability to tolerate the therapy and/or impacts the efficacy of the treatment.

Given the important role of dendritic cells in immunity, derailed dendritic cell functions have been implicated in diseases such as cancer and autoimmune diseases. For example, cancer cells may evade immune detection and destruction by crippling dendritic cell functionality through prevention of dendritic cell recruitment and activation. In addition, dendritic cells have been found in the brain during central nervous system inflammation and may be involved in the pathogenesis of autoimmune diseases in the brain.

One mechanism by which cancers evade immune detection and destruction is by crippling dendritic cell functionality through prevention of dendritic cell (DC) recruitment and activation. Accordingly, there remains a need for cancer therapies that can effectively derail tumor evasion and enhance anti-tumor immunity as mediated, for example, by dendritic cells.

wdt-5

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DESCRIPTION

ABECMA is a BCMA-directed genetically modified autologous T cell immunotherapy product consisting of a patient’s own T cells that are harvested and genetically modified ex vivo through transduction with an anti-BCMA02 chimeric antigen receptor (CAR) lentiviral vector (LVV). Autologous T cells transduced with the anti-BCMA02 CAR LVV express the anti-BCMA CAR on the T cell surface. The CAR is comprised of a murine extracellular single-chain variable fragment (scFv) specific for recognizing B cell maturation antigen (BCMA) followed by a human CD8α hinge and transmembrane domain fused to the T cell cytoplasmic signaling domains of CD137 (4-1BB) and CD3ζ chain, in tandem. Binding of ABECMA to BCMA-expressing target cells leads to signaling initiated by CD3ζ and 4-1BB domains, and subsequent CAR-positive T cell activation. Antigen-specific activation of ABECMA results in CAR-positive T cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells.

ABECMA is prepared from the patient’s peripheral blood mononuclear cells (PBMCs), which are obtained via a standard leukapheresis procedure. The mononuclear cells are enriched for T cells, through activation with anti-CD3 and anti-CD28 antibodies in the presence of IL-2, which are then transduced with the replication-incompetent lentiviral vector containing the anti-BCMA CAR transgene. The transduced T cells are expanded in cell culture, washed, formulated into a suspension, and cryopreserved. The product must pass a sterility test before release for shipping as a frozen suspension in one or more patient-specific infusion bag(s). The product is thawed prior to infusion back into the patient [see DOSAGE AND ADMINISTRATION and HOW SUPPLIED/Storage And Handling].

The ABECMA formulation contains 50% Plasma-Lyte A and 50% CryoStor® CS10, resulting in a final DMSO concentration of 5%.

FDA approves idecabtagene vicleucel for multiple myeloma

On March 26, 2021, the Food and Drug Administration approved idecabtagene vicleucel (Abecma, Bristol Myers Squibb) for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. This is the first FDA-approved cell-based gene therapy for multiple myeloma.

Idecabtagene vicleucel is a B-cell maturation antigen (BCMA)-directed genetically modified autologous chimeric antigen receptor (CAR) T-cell therapy. Each dose is customized using a patient’s own T-cells, which are collected and genetically modified, and infused back into the patient.

Safety and efficacy were evaluated in a multicenter study of 127 patients with relapsed and refractory multiple myeloma who received at least three prior lines of antimyeloma therapies; 88% had received four or more prior lines of therapies. Efficacy was evaluated in 100 patients who received idecabtagene vicleucel in the dose range of 300 to 460 x 106 CAR-positive T cells. Efficacy was established based on overall response rate (ORR), complete response (CR) rate, and duration of response (DOR), as evaluated by an Independent Response committee using the International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma.

The ORR was 72% (95% CI: 62%, 81%) and CR rate was 28% (95% CI 19%, 38%). An estimated 65% of patients who achieved CR remained in CR for at least 12 months.

The idecabtagene vicleucel label carries a boxed warning for cytokine release syndrome (CRS), neurologic toxicities, hemophagocytic lymphohistiocytosis/ macrophage activation syndrome, and prolonged cytopenias. The most common side effects of idecabtagene vicleucel include CRS, infections, fatigue, musculoskeletal pain, and hypogammaglobulinemia.

Idecabtagene vicleucel is approved with a risk evaluation and mitigation strategy requiring that healthcare facilities that dispense the therapy must be specially certified to recognize and manage CRS and nervous system toxicities. To evaluate long-term safety, the FDA is requiring the manufacturer to conduct a post-marketing observational study involving patients treated with idecabtagene vicleucel.

The recommended dose range for idecabtagene vicleucel is 300 to 460 × 106 CAR-positive T cells. View full prescribing information for Abecma.

This application was granted breakthrough therapy designation and orphan drug designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

FDA D.I.S.C.O. Burst Edition: FDA approval of ABECMA (idecabtagene vicleucel) the first FDA approved cell-based gene therapy for the treatment of adult patients with relapsed or refractory multiple myeloma

Welcome back to the D.I.S.C.O., FDA’s Drug Information Soundcast in Clinical Oncology, Burst Edition, brought to you by FDA’s Division of Drug Information in partnership with FDA’s Oncology Center of Excellence. Today we have another quick update on a recent FDA cancer therapeutic approval.

On March 26, 2021, the FDA approved idecabtagene vicleucel (brand name Abecma) for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. This is the first FDA-approved cell-based gene therapy for multiple myeloma.

Idecabtagene vicleucel is a B-cell maturation antigen-directed genetically modified autologous chimeric antigen receptor T-cell therapy. Each dose is customized using a patient’s own T-cells, which are collected and genetically modified, and infused back into the patient.

Safety and efficacy were evaluated in a multicenter study of 127 patients with relapsed and refractory multiple myeloma who received at least three prior lines of antimyeloma therapies, 88% of whom had received four or more prior lines of therapies. Efficacy was evaluated in 100 patients who received idecabtagene vicleucel and was established based on overall response rate, complete response rate, and duration of response, as evaluated by an Independent Response committee using the International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma.

The overall response rate was 72% and complete response rate was 28%. An estimated 65% of patients who achieved complete response remained in complete response for at least 12 months.

The idecabtagene vicleucel label carries a boxed warning for cytokine release syndrome, neurologic toxicities, hemophagocytic lymphohistiocytosis/ macrophage activation syndrome, and prolonged cytopenias. Idecabtagene vicleucel is approved with a risk evaluation and mitigation strategy requiring that healthcare facilities dispensing the therapy must be specially certified to recognize and manage cytokine release syndrome and nervous system toxicities. To evaluate long-term safety, the FDA is requiring the manufacturer to conduct a post-marketing observational study involving patients treated with idecabtagene vicleucel.

Full prescribing information for this approval can be found on the web at www.fda.gov, with key word search “Approved Cellular and Gene Therapy Products”.

Health care professionals should report serious adverse events to FDA’s MedWatch Reporting System at www.fda.gov/medwatch.

Follow the Division of Drug Information on Twitter @FDA_Drug_InfoExternal Link Disclaimer and the Oncology Center of Excellence @FDAOncologyExternal Link Disclaimer. Send your feedback via email to FDAOncology@fda.hhs.gov. Thanks for tuning in today to the DISCO Burst Edition.

PAT

WO 2019148089

In various aspects, the present invention relates to XCR1 binding agents having at least one targeting moiety that specifically binds to XCR1. In various embodiments, these XCR1 binding agents bind to, but do not functionally modulate ( e.g . partially or fully neutralize) XCR1. Therefore, in various embodiments, the present XCR1 binding agents have use in, for instance, directly or indirectly recruiting a XCR1-expressing cell to a site of interest while still allowing the XCR1-expressing cell to signal via XCR1 (i.e. the binding of the XCR1 binding agent does not reduce or eliminate XCR1 signaling at the site of interest). In various embodiments, the XCR-1 binding agent functionally modulates XCR1. In an embodiment, the targeting moiety is a single domain antibody (e.g. VHH, HUMABODY, scFv, on antibody). In various embodiments, the XCR1 binding agent further comprises a signaling agent, e.g., without limitation, an interferon, an interleukin, and a tumor necrosis factor, that may be modified to attenuate activity. In various embodiments, the XCR1 binding agent comprises additional targeting moieties that bind to other targets (e.g. antigens, receptor) of interest. In an embodiment, the other targets (e.g. antigens, receptor) of interest are present on tumor cells. In another embodiment, the other targets (e.g. antigens, receptor) of interest are present on immune cells. In some embodiments, the present XCR1 binding agent may directly or indirectly recruit an immune cell (e.g. a dendritic cell) to a site of action (such as, by way of non-limiting example, the tumor microenvironment). In some embodiments, the present XCR1 binding agent facilitates the presentation of antigens (e.g., tumor antigens) by dendritic cells.

In various embodiments, the present XCR binding agent or targeting moiety of the present chimeric proteins comprises the heavy chain of SEQ ID NO: 223 and/or the light chain of SEQ ID NO: 224, or a variant thereof (e.g. an amino acid sequence having at least about 90%, or at least about 93%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, identity with SEQ ID NO: 223 and/or SEQ ID NO: 224).

In various embodiments, the present XCR binding agent or targeting moiety of the present chimeric proteins comprises a heavy chain CDR 1 of SHNLH (SEQ ID NO: 225), heavy chain CDR 2 of AIYPGNGNTAYNQKFKG (SEQ ID NO: 226), and heavy chain CDR 3 of WGSVVGDWYFDV (SEQ ID NO: 227) and/or a light chain CDR 1 of RSSLGLVHRNGNTYLH (SEQ ID NO: 228), light chain CDR 2 of KVSHRFS (SEQ ID NO: 229), and light chain CDR 3 of SQSTFIVPWT (SEQ ID NO: 230), or a variant thereof (e.g. with four or fewer amino acid substitutions, or with three or fewer amino acid substitutions, or with two or fewer amino acid substitutions, or with one amino acid substitution).

In various embodiments, the present XCR binding agent or targeting moiety of the present chimeric proteins comprises a heavy chain CDR 1 of SHNLH (SEQ ID NO: 225), heavy chain CDR 2 of AIYPGNGNTAYNQKFKG (SEQ ID NO: 226), and heavy chain CDR 3 of WGSVVGDWYFDV (SEQ ID NO: 227).

Illustrative Disease Modifying Therapies

EXAMPLES

Example 1. Identification and Characterization of Human XCR1 Ab AFNs

As used in this Example and associated figures,“AFN” is a chimera of the anti-Xcr1 5G7 antibody and human IFNa2 with an R149A mutation.

AFNs were made based on the 5G7 anti-hXcr1 Ab using the intact (full) Ab or a scFv format.

The 5G7 heavy chain is:

QAYLQQSGAELVRPGASVKMSCKASGYTFTSHNLHWVKQTPRQGLQWIGAIYPGNGNTAYNQKFKGKATLTVD

KSSSTAYMQLSSLTSDDSAVYFCARWGSVVGDWYFDVWGTGTTVTVSSASTKGPSVFPLAPCSRSTSESTAAL

GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSNFGTQTYTCNVDHKPSNTKVDKTVE

RKCCVECPPCPAPPAAAPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVQFNWYVDGVEVHNAKTKPREE

QFNSTFRVVSVLTWHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLV

KGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS

LSPGK (SEQ ID NO: 223)

The 5G7 light chain is:

DWMTQTPLSLPVTLGNQASIFCRSSLGLVHRNGNTYLHWYLQKPGQSPKLLIYKVSHRFSGVPDRFSGSGSGT DFTLKISRVEAEDLGVYFCSQSTHVPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 224)

5G7 Heavy chain CDR 1 is SHNLH (SEQ ID NO: 225), Heavy chain CDR 2 is AIYPGNGNTAYNQKFKG (SEQ ID NO: 226), Heavy chain CDR 3 is WGSVVGDWYFDV (SEQ ID NO: 227). 5G7 Light chain CDR 1 is RSSLGLVHRNGNTYLH (SEQ ID NO: 228), Light chain CDR 2 is KVSHRFS (SEQ ID NO: 229), and Light chain CDR 3 is SQSTHVPWT (SEQ ID NO: 230).

The sequence of hulFNa2(R149A) is:

CDLPQTHSLGSRRTLMLLAQMRKISLFSCLKDRHDFGFPQEEFGNQFQKAETIPVLHEMIQQIFNLFSTKDSSAA WDETLLDKFYTELYQQLNDLEACVIQGVGVTETPLMKEDSILAVRKYFQRITLYLKEKKYSPCAWEVVRAEIMASF SLSTNLQESLRSKE (SEQ ID NO: 231).

In case of the intact Ab AFN, the 5G7 Ab heavy chain was fused to h I FN a2_R149A (human IFNal with a R149A mutation) via a flexible (GGS)2oG-linker and co-expressed with the 5G7 Ab light chain (sequences shown below). 5G7 scFv-AFN was constructed by linking the Ab VL and VH domains via a (GGGS)4 linker and followed by a (GGS)2o-linker and the sequence encoding hlFNa2_R149A. Recombinant proteins, cloned in the pcDNA3.4 expression-vector, were produced in ExpiCHO cells (Thermo Fisher Scientific) and purified on HisPUR spin plates (Thermo Fisher Scientific) according to the manufacturer’s instructions.

To test binding of the AFNs, parental HL1 16 and HL1 16 cells stably expressing hXcrl (HL116-hXcr1) were incubated with a serial dilution AFN for two hours at 4°C. Binding was detected using THE™ HIS antibody-FITC (GenScript) and measured on a MACSQuant X instrument (Miltenyi Biotec) and analysed using the FlowLogic software (Miltenyi Biotec). Data in Figures 1A and 1 B clearly show that both 5G7 Ab-AFN and 5G7 scFv bind specifically to hXcrl expressing cells.

Biological activity was measured on parental HL1 16 cells (an IFN responsive cell-line stably transfected with a p6-16 luciferase reporter) and the derived HL116-hXcr1 cells. Cells were seeded overnight and stimulated for 6 hours with a serial dilution 5G7 AFNs. Luciferase activity was measured on an EnSight Multimode Plate Reader (Perkin Elmer). Data in Figures 2A and 2B clearly illustrate that 5G7 AFNs, in the intact Ab format or as scFv, are clearly more active on cells expressing hXcrl compared to parental cells, illustrating that it is possible to restore signaling of an IFNa2 mutant by specific targeting to hXcrl .

Example 2. Identification and Characterization of Mouse Xcr1 Ab AFNs

As used in this Example and associated figures,“AFN” is a chimera of the anti-Xcr1 MAARX10 antibody and human IFNa2 with Q124R mutation.

Similar to the anti-human Xcr1 Ab, AFNs based on the MARX10 anti-mouse Xcr1 Ab were made, as intact Ab or as scFv. In case of the intact Ab AFN, the MARX10 Ab heavy chain was fused to hlFNa2_Q124R (human IFNa2 with Q124R mutation) via a flexible (GGS)2oG-linker and co-expressed with the MARX10 Ab light chain. scFv-AFN was constructed by linking the Ab VL and VH domains, in VH-VL (scFv(1 )) or VL-VH (scFv(2)) orientation, via a (GGGS)4 linker and followed by a (GGS)2o-linker and h I FN a2_Q 124R.

Selectivity of AFNs (produced and purified as described above for the human Xcr1 Ab AFNs) was tested by comparing binding at 2.5 pg/ml to MOCK or mouse Xcr1 transfected Hek293T cells. Binding was detected using THE™ HIS antibody-FITC (GenScript) and measured on a MACSQuant X instrument (Miltenyi Biotec) and analysed using the FlowLogic software (Miltenyi Biotec). Data in Figure 3 clearly show that all three specifically bind to mXcrl expressing cells.

REF

https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-idecabtagene-vicleucel-multiple-myeloma

 New England Journal of Medicine (2021), 384(8), 705-716

https://www.rxlist.com/abecma-drug.htm#indications

///////////Idecabtagene vicleucel,  breakthrough therapy designation, orphan drug designation, FDA 2021, APPROVALS 2021, Bb2121, Bb , ABECMA

Manufacturer: Celgene Corporation, a Bristol-Myers Squibb Company
Indications:

  • Treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.

Product Information

Supporting Documents

Loncastuximab tesirine


ZYNLONTA™ (loncastuximab tesirine-lpyl) Structural Formula - Illustration
Pharmaceuticals 14 00442 g047 550

Loncastuximab tesirine

ZYNLONTA FDA APPROVED 2021/4/23

FormulaC6544H10048N1718O2064S52
Exact mass147387.9585
CAS1879918-31-6
EfficacyAntineoplasitc, Anti-CD19 antibody
  DiseaseDiffuse large B-cell lymphoma not otherwise specified [DS:H02434]
CommentAntibody-drug conjugate
Treatment of hematological cancers

ロンカスツキシマブテシリン; ADCT-402, ADCX 19

Immunoglobulin G1, anti-​(human CD19 antigen) (human-​Mus musculus monoclonal RB4v1.2 γ1-​chain)​, disulfide with human-​Mus musculus monoclonal RB4v1.2 κ-​chain, dimer, bis(thioether) with N-​[31-​(3-​mercapt-​2,​5-​dioxo-​1-​pyrrolidinyl)​-​1,​29-​dioxo-​4,​7,​10,​13,​16,​19,​22,​25-​octaoxa-​28-​azahentriacont-​1-​yl]​-​L-​valyl-​N-​[4-​[[[[(11S,​11aS)​-​8-​[[5-​[[(11aS)​-​5,​11a-​dihydro-​7-​methoxy-​2-​methyl-​5-​oxo-​1H-​pyrrolo[2,​1-​c]​[1,​4]​benzodiazepin-​8-​yl]​oxy]​pentyl]​oxy]​-​11,​11a-​dihydro-​11-​hydroxy-​7-​methoxy-​2-​methyl-​5-​oxo-​1H-​pyrrolo[2,​1-​c]​[1,​4]​benzodiazepin-​10(5H)​-​yl]​carbonyl]​oxy]​methyl]​phenyl]​-​L-​alaninamide

NEW DRUG APPROVALS

ONETIME

$10.00

Monoclonal antibody
TypeWhole antibody
SourceHumanized
TargetCD19
Clinical data
Trade namesZynlonta
Other namesADCT-402, loncastuximab tesirine-lpyl
License dataUS DailyMedLoncastuximab_tesirine
ATC codeNone
Legal status
Legal statusUS: ℞-only [1]
Identifiers
CAS Number1879918-31-6
DrugBankDB16222
ChemSpidernone
UNII7K5O7P6QIU
KEGGD11338
Chemical and physical data
FormulaC6544H10048N1718O2064S52
Molar mass147481.45 g·mol−1
NAMEDOSAGESTRENGTHROUTELABELLERMARKETING STARTMARKETING END  
ZynlontaInjection, powder, lyophilized, for solution5 mg/1mLIntravenousADC Therapeutics America, Inc.2021-04-30Not applicableUS flag 

Loncastuximab tesirine-lpyl is a CD19-directed antibody and alkylating agent conjugate, consisting of a humanized IgG1 kappa monoclonal antibody conjugated to SG3199, a pyrrolobenzodiazepine (PBD) dimer cytotoxic alkylating agent, through a protease-cleavable valinealanine linker. SG3199 attached to the linker is designated as SG3249, also known as tesirine.

ZYNLONTA™ (loncastuximab tesirine-lpyl) Structural Formula - Illustration

Loncastuximab tesirine-lpyl has an approximate molecular weight of 151 kDa. An average of 2.3 molecules of SG3249 are attached to each antibody molecule. Loncastuximab tesirine-lpyl is produced by chemical conjugation of the antibody and small molecule components. The antibody is produced by mammalian (Chinese hamster ovary) cells, and the small molecule components are produced by chemical synthesis.

ZYNLONTA (loncastuximab tesirine-lpyl) for injection is supplied as a sterile, white to off-white, preservative-free, lyophilized powder, which has a cake-like appearance, for intravenous infusion after reconstitution and dilution. Each single-dose vial delivers 10 mg of loncastuximab tesirine-lpyl, L-histidine (2.8 mg), L-histidine monohydrochloride (4.6 mg), polysorbate 20 (0.4 mg), and sucrose (119.8 mg). After reconstitution with 2.2 mL Sterile Water for Injection, USP, the final concentration is 5 mg/mL with a pH of approximately 6.0.

Loncastuximab tesirine , sold under the brand name Zynlonta, is used for the treatment of large B-cell lymphoma. It is an antibody-drug conjugate (ADC) composed of a humanized antibody targeting the protein CD19, which is expressed in a wide range of B cell hematological tumors.[2] The experimental drug, developed by ADC Therapeutics is being tested in clinical trials for the treatment of B-cell non-Hodgkin lymphoma (NHL) and B-cell acute lymphoblastic leukemia (ALL).

On April 23, 2021, the Food and Drug Administration granted accelerated approval to loncastuximab tesirine-lpyl (Zynlonta, ADC Therapeutics SA), a CD19-directed antibody and alkylating agent conjugate, for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low grade lymphoma, and high-grade B-cell lymphoma.

Approval was based on LOTIS-2 (NCT03589469), an open-label, single-arm trial in 145 adult patients with relapsed or refractory DLBCL or high-grade B-cell lymphoma after at least two prior systemic regimens. Patients received loncastuximab tesirine-lpyl 0.15 mg/kg every 3 weeks for 2 cycles, then 0.075 mg/kg every 3 weeks for subsequent cycles. Patients received treatment until progressive disease or unacceptable toxicity.

The main efficacy outcome measure was overall response rate (ORR), as assessed by an independent review committee using Lugano 2014 criteria. The ORR was 48.3% (95% CI: 39.9, 56.7) with a complete response rate of 24.1% (95% CI: 17.4, 31.9). After a median follow-up of 7.3 months, median response duration  was 10.3 months (95% CI: 6.9, NE). Of the 70 patients who achieved objective responses, 36% were censored for response duration prior to 3 months.

Most common (≥20%) adverse reactions in patients receiving loncastuximab tesirine-lpyl, including laboratory abnormalities, are thrombocytopenia, increased gamma-glutamyltransferase, neutropenia, anemia, hyperglycemia, transaminase elevation, fatigue, hypoalbuminemia, rash, edema, nausea, and musculoskeletal pain.

The prescribing information provides warnings and precautions for adverse reactions including edema and effusions, myelosuppression, infections, and cutaneous reactions.

The recommended loncastuximab tesirine-lpyl dosage is 0.15 mg/kg every 3 weeks for 2 cycles, then 0.075 mg/kg every 3 weeks for subsequent cycles, by intravenous infusion over 30 minutes on day 1 of each cycle (every 3 weeks). Patients should be premedicated with dexamethasone 4 mg orally or intravenously twice daily for 3 days beginning the day before loncastuximab tesirine-lpyl.

Technology

The humanized monoclonal antibody is stochastically conjugated via a valine-alanine cleavable, maleimide linker to a cytotoxic (anticancer) pyrrolobenzodiazepine (PBD) dimer. The antibody binds to CD19, a protein which is highly expressed on the surface of B-cell hematological tumors[3] including certain forms of lymphomas and leukemias. After binding to the tumor cells the antibody is internalized, the cytotoxic drug PBD is released and the cancer cells are killed. PBD dimers are generated out of PBD monomers, a class of natural products produced by various actinomycetes. PBD dimers work by crosslinking specific sites of the DNA, blocking the cancer cells’ division that cause the cells to die. As a class of DNA-crosslinking agents they are significantly more potent than systemic chemotherapeutic drugs.[4]

Clinical trials

Two phase I trials are evaluating the drug in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma and relapsed or refractory B-cell acute lymphoblastic leukemia.[5] At the 14th International Conference on Malignant Lymphoma interim results from a Phase I, open-label, dose-escalating study designed to evaluate the treatment of loncastuximab tesirine in relapsed or refractory non-Hodgkin’s lymphoma were presented.[6] Among the patients enrolled at the time of the data cutoff the overall response rate was 61% in the total patient population (42% complete response and 19% partial response) and in patients with relapsing or refractory diffuse large B-cell lymphoma (DLBCL) the overall response rate was 57% (43% complete response and 14% partial response).[7][8]

Orphan drug designation

Loncastuximab tesirine was granted Orphan Drug Designation by the U.S. Food and Drug Administration (FDA) for the treatment of diffuse large B-cell lymphoma and mantle cell lymphoma.[9]

References

  1. ^ https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761196s000lbl.pdf
  2. ^ WHO Drug Information: International Nonproprietary Names for Pharmaceutical Substances
  3. ^ Wang K, Wei G, Liu D (November 2012). “CD19: a biomarker for B cell development, lymphoma diagnosis and therapy”Experimental Hematology & Oncology1 (1): 36. doi:10.1186/2162-3619-1-36PMC 3520838PMID 23210908.
  4. ^ “Pyrrolobenzodiazepine”ADC Review.
  5. ^ Clinical trial number NCT02669017 for “ADCT-402 in B-NHL” at ClinicalTrials.gov
  6. ^ Kahl B, Hamadani M, Caimi PF, Reid EG, Havenith K, He S, Feingold JM, O’Connor O (June 2017). “First clinical results of ADCT‐402, a novel pyrrolobenzodiazepine-based antibody drug conjugate (ADC), in relapsed/refractory B‐cell linage NHL” (PDF). Hematol Oncol35 (S2): 49–51. doi:10.1002/hon.2437_33.
  7. ^ “First clinical results of ADCT-402”ADC Review.
  8. ^ Bainbridge K. “Grandfather fighting deadly cancer reveals scans of tumors after testing new drug”Mirror.
  9. ^ “ADCT-402 Orphan Drug Designation” (PDF). ADC Therapeutics press release.

External links

https://www.fda.gov/drugs/fda-grants-accelerated-approval-loncastuximab-tesirine-lpyl-large-b-cell-lymphoma

/////////Loncastuximab tesirine, FDA 2021, APPROVALS 2021, ZYNLONTA, ロンカスツキシマブテシリン, ORPHAN DRUG, ADCT-402, priority review, ADCX 19

ZyCoV-D


Zydus Cadila Hopes To Get Clearance To Its Covid Vaccine ZyCoV-D From Indian Authorities Soon - YouTube

ZyCoV-D

CAS 2541524-47-2 

DNA vaccine construct encoding a spike protein antigen of SARS-CoV-2 virus (Zydus-Cadila)

http://ctri.nic.in/Clinicaltrials/showallp.php?mid1=51254&EncHid=&userName=ZyCoV-D

bioRxiv (2021), 1-26. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423510/

ZyCoV-D | (CTRI/2020/07/026352, 2020CTRI/2020/07/026352, 2020Myupchar, 2020)ZYDUS CADILA

ZyCoV-D is a genetically engineered DNA plasmid based vaccine encoding for the membrane proteins of the virus. The clinical trials to study the immunogenicity, and safety of the vaccine, will administer three doses at an interval of 28 days in 1048 individuals.

Phase 1/2: CTRI/2020/07/026352

Vaccine description
TargetSARS-CoV-2
Vaccine typeDNA
Clinical data
Routes of
administration
Intradermal
ATC codeNone
Identifiers
DrugBankDB15892
Part of a series on the
COVID-19 pandemic
SARS-CoV-2 (virus)COVID-19 (disease)
showTimeline
showLocations
showInternational response
showMedical response
showImpact
 COVID-19 portal

ZyCoV-D is a DNA plasmid based COVID-19 vaccine being developed by Cadila Healthcare with support from the Biotechnology Industry Research Assistance Council.

The ZYCOV-D vaccine candidate was developed by Cadila Healthcare Ltd. based in India1. The vaccine was developed using a DNA vaccine platform with a non-replicating and non-integrating plasmid carrying the gene of interest3. Once the plasmid DNA is introduced into host cells and the viral protein is translated, it elicits a strong immune response, stimulating the humoral and cellular components of the immune system3. The DNA vaccine platform offers minimal biosafety requirements, more improved vaccine stability, and lower cold chain requirements3. Phase I clinical trials of this vaccine candidate were completed in July 2020, with the company reporting successful dosing and tolerance1,2. As of August, 2020 the candidate is in Phase II clinical trials1.

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Clinical research

Phase I and II trials

In February 2020, Cadila Healthcare decided to develop a DNA plasmid based COVID-19 vaccine at their Vaccine Technology Centre (VTC) in Ahmedabad.[1] The vaccine candidate was able to pass the pre-clinical trials on animal models successfully. A report of the study was made available via bioRxiv.[2] Thereafter, human trials for Phase I and II were approved by the regulator.[3]

The Phase II trials of the vaccine candidate were conducted in over 1,000 volunteers as part of the adaptive Phase I/II multi-centric, dose escalation, randomised, double-blind placebo controlled method.[4][5]

Phase III trials

In November 2020, the company announced it would test the vaccine candidate on 30,000 patients in Phase III trials.[6] The vaccine would be given out in three doses at five sites across four cities of India.[7] In January 2021, the Drugs Controller General of India (DCGI) granted permission to conduct the Phase III clinical trials for 28,216 Indian participants.[8][9]

In April 2021, the company reported that they expected to have initial data for the Phase III trials by May 2021.[10]

Production

On 23 April 2021, production of the ZyCoV-D vaccine was started, with a yearly capacity of 240 million doses. It is expected to get emergency use authorization in May or June.[11]

References

  1. ^ “Zydus Cadila launches a fast tracked programme to develop vaccine for the novel coronavirus, 2019-nCoV (COVID-19)”(PDF). http://www.zyduscadila.comCadila Healthcare.
  2. ^ Dey A, Rajanathan C, Chandra H, Pericherla HP, Kumar S, Choonia HS, et al. (26 January 2021). “Immunogenic Potential of DNA Vaccine candidate, ZyCoV-D against SARS-CoV-2 in Animal Models”. bioRxiv: 2021.01.26.428240. doi:10.1101/2021.01.26.428240S2CID 231777527.
  3. ^ “A prospective, randomized, adaptive, phase I/II clinical study to evaluate the safety and immunogenicity of Novel Corona Virus −2019-nCov vaccine candidate of M/s Cadila Healthcare Limited by intradermal route in healthy subjects”ctri.nic.inClinical Trials Registry India. 15 December 2020. CTRI/2020/07/026352. Archived from the original on 22 November 2020.
  4. ^ “Zydus Cadila’s ZyCov-D vaccine found to be ‘safe and immunogenic'”@businesslineThe Hindu. 24 December 2020.
  5. ^ Rawat K, Kumari P, Saha L (February 2021). “COVID-19 vaccine: A recent update in pipeline vaccines, their design and development strategies”European Journal of Pharmacology892: 173751. doi:10.1016/j.ejphar.2020.173751PMC 7685956PMID 33245898.
  6. ^ Thacker T (7 November 2020). “Zydus Cadila to test ZyCoV-D on 30,000 patients in Phase-3 trials”The Economic Times.
  7. ^ “Covid 19 vaccine in India: Zydus Cadila begins enrolment for Phase 3 trial of ZyCoV-D in 4 cities”The Financial Express. 22 January 2021.
  8. ^ “DBT-BIRAC supported indigenously developed DNA Vaccine Candidate by Zydus Cadila, approved for Phase III clinical trials”pib.gov.inPress Information Bureau. 3 January 2021.
  9. ^ “Novel Corona Virus-2019-nCov vaccine by intradermal route in healthy subjects”ctri.nic.in. Clinical Trials Registry – India. Retrieved 10 April 2021.
  10. ^ Das, Sohini (22 April 2021). “Cadila Healthcare testing two-shot regimen for ZyCoV-D, data likely by May”Business Standard India.
  11. ^ Writer, Staff (24 April 2021). “Cadila Healthcare starts production of Covid vaccine candidate”mint. Retrieved 27 April 2021.

Zydus Cadila Covid vaccine close to getting approved in India, says MD Sharvil Patel

https://www.indiatoday.in/coronavirus-outbreak/vaccine-updates/story/zydus-cadila-covid-vaccine-close-to-getting-approved-in-india-says-md-sharvil-patel-1800132-2021-05-08

In an exclusive interview with India Today TV, Managing Director of Zydus Cadila Dr Sharvil Patel said the company’s Covid vaccine candidate ZyCoV-D against the Covid-19 infection is very close to getting approved in India. They are likely to apply for emergency use authorisation this month.

Ahmedabad-based pharmaceutical company Zydus Cadila is likely to submit the application for emergency use authorisation of its Covid-19 vaccine candidate ‘ZyCoV-D’ in India this month. The company is confident that the vaccine will be approved in May itself. The company plants to produce one crore doses of its ‘painless’ Covid-19 vaccine per month.

If approved, ZyCoV-D will be the fourth vaccine to be used in India’s Covid-19 vaccination drive. Made in India, the company plans to ramp up the vaccine’s production to 3-4 crore doses per month and is already in talks with two other manufacturing companies for the same

Although the vaccine should ideally be stored between 2 and 8 degrees Celsius, it remains stable even at room temperature conditions at 25 degrees Celsius. It is easy to administer, the developers said, and will be administered via intradermal injection.

If approved for emergency use, ZyCoV-D could help India fill the vacuum of vaccine doses currently being experienced in the country’s immunisation drive.

Earlier in April, Zydus Cadila announced that its drug Virafin had received restricted emergency use approval from the Drug Controller General of India for the treatment of mild cases of Covid-19.

In an exclusive interview with India Today TV, Sharvil Patel sheds details on all aspects of the Covid-19 vaccine ZyCoV-D.

When asked the status of Covid vaccine candidate ZyCoV-D and when exactly Zydus Cadila would apply for emergency use authorisation in India, Dr Sharvil Patel said the vaccine was getting very close to getting approved in the country.

“I am very happy to say that India’s first indigenously developed DNA vaccine candidate against Covid, which is our ZyCoV-D, is getting very close to approval,” he said.

“We have almost completed all our recruitment for the clinical trials. We have, by far, recruited the largest number of patients for a Covid vaccine trial in India. The number of volunteers who have been vaccinated as a part of the trial is 28,000,” Sharvil Patel said.

Sharvil Patel also said that his company has also included children in the 12-17 age group for the vaccine trials.

He said, “The recruitment holds very important milestones in terms of cohorts because not only have we included the elderly and those with co-morbidities, but also children in the age group of 12 to 17 years.”

Sharvil Patel said as soon as the efficacy data is obtained, Sydus Cadila will file for emergency use authorisation. As soon as the approval is granted, Zydus Cadila will start production of Covid-19 vaccines from July, he said.

“We hope to see our efficacy data in the middle of May. As soon as we see strong efficacy which correlates to the vaccine’s strong immunogenicity in Phase 2, we will file for emergency use authorization. We hope to produce a good quantity of the vaccine from July onwards to make sure it is available to the people. That is the need of the hour right now,” Sharvil Patel said.

He said by May the company will be in a position to talk to the regulators about the restricted use of the Covid-19 vaccine. “The regulatory process is a rolling one. I believe the regulators look at the data in a short period of time,” Sharvil Patel said.

“We have submitted a lot of data already so that it will aid the regulators once we provide them with the efficacy results. We are, hence, expecting to get the approval in May itself,” Sharvil Patel said.

///////////ZyCoV-D, COVID 19, CORONA VIRUS, VACCINE, INDIA 2021, APPROVALS 2021, SARS-CoV-2

Dostarlimab


(Heavy chain)
EVQLLESGGG LVQPGGSLRL SCAASGFTFS SYDMSWVRQA PGKGLEWVST ISGGGSYTYY
QDSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCASPY YAMDYWGQGT TVTVSSASTK
GPSVFPLAPC SRSTSESTAA LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS
LSSVVTVPSS SLGTKTYTCN VDHKPSNTKV DKRVESKYGP PCPPCPAPEF LGGPSVFLFP
PKPKDTLMIS RTPEVTCVVV DVSQEDPEVQ FNWYVDGVEV HNAKTKPREE QFNSTYRVVS
VLTVLHQDWL NGKEYKCKVS NKGLPSSIEK TISKAKGQPR EPQVYTLPPS QEEMTKNQVS
LTCLVKGFYP SDIAVEWESN GQPENNYKTT PPVLDSDGSF FLYSRLTVDK SRWQEGNVFS
CSVMHEALHN HYTQKSLSLS LGK
(Light chain)
DIQLTQSPSF LSAYVGDRVT ITCKASQDVG TAVAWYQQKP GKAPKLLIYW ASTLHTGVPS
RFSGSGSGTE FTLTISSLQP EDFATYYCQH YSSYPWTFGQ GTKLEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(Disulfide bridge: H22-H96, H130-L214, H143-H199, H222-H’222, H225-H’225, H257-H317, H363-H421, H’22-H’96, H’130-L’214, H’143-H’199, H’257-H’317, H’363-H’421, L23-L88, L134-L194, L’23-L’88, L’194-L’134)

>Heavy Chain
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSTISGGGSYTYY
QDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASPYYAMDYWGQGTTVTVSSASTK
GPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS
LSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFP
PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVS
VLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVS
LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFS
CSVMHEALHNHYTQKSLSLSLGK
>Light Chain
DIQLTQSPSFLSAYVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASTLHTGVPS
RFSGSGSGTEFTLTISSLQPEDFATYYCQHYSSYPWTFGQGTKLEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
References:
  1. Statement on a Nonproprietary Name Adopted by the USAN Council: Dostarlimab [Link]

Dostarlimab

Immunoglobulin G4, anti-​(programmed cell death protein 1 (PDCD1)​) (humanized clone ABT1 γ4-​chain)​, disulfide with humanized clone ABT1 κ-​chain, dimer

Protein Sequence

Sequence Length: 1314, 443, 443, 214, 214multichain; modified (modifications unspecified)

  • GSK-4057190
  • GSK4057190
  • TSR 042
  • TSR-042
  • WBP-285
  • ANB 011
FormulaC6420H9832N1680O2014S44
CAS2022215-59-2
Mol weight144183.6677

Jemperli FDA 2021/4/22 AND EMA 2021/4/21

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Dostarlimab, sold under the brand name Jemperli, is a monoclonal antibody medication used for the treatment of endometrial cancer.[1][2][3][4]

The most common adverse reactions (≥20%) were fatigue/asthenia, nausea, diarrhea, anemia, and constipation.[1][2] The most common grade 3 or 4 adverse reactions (≥2%) were anemia and transaminases increased.[1][2]

Dostarlimab is a programmed death receptor-1 (PD-1)–blocking antibody.[1][2]

Dostarlimab was approved for medical use in the United States in April 2021.[1][2][5]

NAMEDOSAGESTRENGTHROUTELABELLERMARKETING STARTMARKETING END  
JemperliInjection50 mg/1mLIntravenousGlaxoSmithKline LLC2021-04-22Not applicableUS flag 

Medical uses

Dostarlimab is indicated for the treatment of adults with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following prior treatment with a platinum-containing regimen.[1][2]

On April 22, 2021, the Food and Drug Administration granted accelerated approval to dostarlimab-gxly (Jemperli, GlaxoSmithKline LLC) for adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following a prior  platinum-containing regimen.

Efficacy was evaluated based on cohort (A1) in GARNET Trial (NCT02715284), a multicenter, multicohort, open-label trial in patients with advanced solid tumors. The efficacy population consisted of 71 patients with dMMR recurrent or advanced endometrial cancer who progressed on or after  a platinum-containing regimen. Patients received dostarlimab-gxly, 500 mg intravenously, every 3 weeks for 4 doses followed by 1,000 mg intravenously every 6 weeks.

The main efficacy endpoints were overall response rate (ORR) and duration of response (DOR), as assessed by blinded independent central review (BICR) according to RECIST 1.1. Confirmed ORR was 42.3% (95% CI: 30.6%, 54.6%). The complete response rate was 12.7% and partial response rate was 29.6%. Median DOR was not reached, with 93.3% of patients having  durations  ≥6 months (range: 2.6 to 22.4 months, ongoing at last assessment).

Serious adverse reactions occurred in 34% of patients receiving dostarlimab-gxly. Serious adverse reactions in >2% of patients included sepsis , acute kidney injury , urinary tract infection , abdominal pain , and pyrexia . The most common adverse reactions (≥20%) were fatigue/asthenia, nausea, diarrhea, anemia, and constipation. The most common grade 3 or 4 adverse reactions (≥2%) were anemia and transaminases increased. Immune-mediated adverse reactions can occur including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.

The recommended dostarlimab-gxly dose and schedule (doses 1 through 4) is 500 mg every 3 weeks. Subsequent dosing, beginning 3 weeks after dose 4, is 1,000 mg every 6 weeks until disease progression or unacceptable toxicity. Dostarlimab-gxly should be administered as an intravenous infusion over 30 minutes.

View full prescribing information for Jemperli.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

FDA also approved the VENTANA MMR RxDx Panel as a companion diagnostic device for selecting endometrial cancer patients for treatment with dostarlimab-gxly.

This review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

This application was granted priority review, and breakthrough therapy designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Side effects

Serious adverse reactions in >2% of patients included sepsis, acute kidney injury, urinary tract infection, abdominal pain, and pyrexia.[1][2]

Immune-mediated adverse reactions can occur including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.[1][2]

History

Like several other available and experimental monoclonal antibodies, it is a PD-1 inhibitor. As of 2020, it is undergoing Phase I/II and Phase III clinical trials.[6][7][8] The manufacturer, Tesaro, announced prelimary successful results from the Phase I/II GARNET study.[6][9][10]

In 2020, the GARNET study announced that Dostarlimab was demonstrating potential to treat a subset of women with recurrent or advanced endometrial cancer.[11]

April 2021, Dostarlimab is approved for the treatment of recurrent or advanced endometrial cancer with deficient mismatch repair (dMMR), which are genetic anomalies abnormalities that disrupt DNA repair.[12]

On April 22, 2021, the Food and Drug Administration granted accelerated approval to dostarlimab-gxly (Jemperli, GlaxoSmithKline LLC).[1] Efficacy was evaluated based on cohort (A1) in GARNET Trial (NCT02715284), a multicenter, multicohort, open-label trial in patients with advanced solid tumors.[1]

Society and culture

Legal status

On 25 February 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Jemperli, intended for the treatment of certain types of recurrent or advanced endometrial cancer.[13] The applicant for this medicinal product is GlaxoSmithKline (Ireland) Limited.[13]

References[

  1. Jump up to:a b c d e f g h i j k “FDA grants accelerated approval to dostarlimab-gxly for dMMR endometri”U.S. Food and Drug Administration(FDA) (Press release). 22 April 2021. Retrieved 22 April 2021. This article incorporates text from this source, which is in the public domain.
  2. Jump up to:a b c d e f g h i “Jemperli- dostarlimab injection”DailyMed. Retrieved 28 April 2021.
  3. ^ Statement On A Nonproprietary Name Adopted By The USAN Council – DostarlimabAmerican Medical Association.
  4. ^ World Health Organization (2018). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 119” (PDF). WHO Drug Information32 (2).
  5. ^ “FDA grants accelerated approval for GSK’s Jemperli (dostarlimab-gxly) for women with recurrent or advanced dMMR endometrial cancer” (Press release). GlaxoSmithKline. 22 April 2021. Retrieved 22 April 2021 – via PR Newswire.
  6. Jump up to:a b Clinical trial number NCT02715284 for “A Phase 1 Dose Escalation and Cohort Expansion Study of TSR-042, an Anti-PD-1 Monoclonal Antibody, in Patients With Advanced Solid Tumors (GARNET)” at ClinicalTrials.gov
  7. ^ Clinical trial number NCT03981796 for “A Study of Dostarlimab (TSR-042) Plus Carboplatin-paclitaxel Versus Placebo Plus Carboplatin-paclitaxel in Patients With Recurrent or Primary Advanced Endometrial Cancer (RUBY)” at ClinicalTrials.gov
  8. ^ Clinical trial number NCT03602859 for “A Phase 3 Comparison of Platinum-Based Therapy With TSR-042 and Niraparib Versus Standard of Care Platinum-Based Therapy as First-Line Treatment of Stage III or IV Nonmucinous Epithelial Ovarian Cancer (FIRST)” at ClinicalTrials.gov
  9. ^ “Data from GARNET study indicates robust activity of dostarlimab in patients with advanced or recurrent endometrial cancer”Tesaro (Press release). Retrieved 1 January 2020.
  10. ^ Scalea B (28 May 2019). “Dostarlimab Effective in Endometrial Cancer Regardless of MSI Status”Targeted Oncology. Retrieved 1 January 2020.
  11. ^ “GSK Presents New Data from the GARNET Study Demonstrating Potential of Dostarlimab to Treat a Subset of Women with Recurrent or Advanced Endometrial Cancer – Drugs.com MedNews”Drugs.com. Retrieved 29 April 2020.
  12. ^ “FDA Approves New Immunotherapy for Endometrial Cancer”Medscape. Retrieved 23 April 2021.
  13. Jump up to:a b “Jemperli: Pending EC decision”European Medicines Agency (EMA) (Press release). 25 February 2021. Retrieved 22 April 2021.

External links

  • “Dostarlimab”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT02715284 for “Study of TSR-042, an Anti-programmed Cell Death-1 Receptor (PD-1) Monoclonal Antibody, in Participants With Advanced Solid Tumors (GARNET)” at ClinicalTrials.gov
  1. Kaplon H, Muralidharan M, Schneider Z, Reichert JM: Antibodies to watch in 2020. MAbs. 2020 Jan-Dec;12(1):1703531. doi: 10.1080/19420862.2019.1703531. [Article]
  2. Temrikar ZH, Suryawanshi S, Meibohm B: Pharmacokinetics and Clinical Pharmacology of Monoclonal Antibodies in Pediatric Patients. Paediatr Drugs. 2020 Apr;22(2):199-216. doi: 10.1007/s40272-020-00382-7. [Article]
  3. Green AK, Feinberg J, Makker V: A Review of Immune Checkpoint Blockade Therapy in Endometrial Cancer. Am Soc Clin Oncol Educ Book. 2020 Mar;40:1-7. doi: 10.1200/EDBK_280503. [Article]
  4. Deshpande M, Romanski PA, Rosenwaks Z, Gerhardt J: Gynecological Cancers Caused by Deficient Mismatch Repair and Microsatellite Instability. Cancers (Basel). 2020 Nov 10;12(11). pii: cancers12113319. doi: 10.3390/cancers12113319. [Article]
  5. FDA Approved Drug Products: Jemperli (dostarlimab-gxly) for intravenous injection [Link]
  6. FDA News Release: FDA grants accelerated approval to dostarlimab-gxly for dMMR endometrial cancer [Link]
  7. Statement on a Nonproprietary Name Adopted by the USAN Council: Dostarlimab [Link]
Monoclonal antibody
TypeWhole antibody
SourceHumanized
TargetPCDP1
Clinical data
Trade namesJemperli
Other namesTSR-042, WBP-285, dostarlimab-gxly
License dataUS DailyMedDostarlimab
Routes of
administration
Intravenous
Drug classAntineoplastic
ATC codeL01XC40 (WHO)
Legal status
Legal statusUS: ℞-only [1][2]
Identifiers
CAS Number2022215-59-2
PubChem SID384585344
DrugBankDB15627
UNIIP0GVQ9A4S5
KEGGD11366
Chemical and physical data
FormulaC6420H9832N1690O2014S44
Molar mass144325.73 g·mol−1

/////////Dostarlimab,  PEPTIDE, ANTINEOPLASTIC, CANCER, ドスタルリマブ , GSK 4057190, GSK4057190, TSR 042, TSR-042, WBP-285, FDA 2021, EU 2021

DEXMETHYLPHENIDATE


Dexmethylphenidate structure.svg

DEXMETHYLPHENIDATE

SynonymsDexmethylphenidate HCl, UNII1678OK0E08, CAS Number19262-68-1, WeightAverage: 269.77
Chemical FormulaC14H20ClNO2

methyl (2R)-2-phenyl-2-[(2R)-piperidin-2-yl]acetate hydrochloride

Thumb
CAS Number40431-64-9 as HCl: 19262-68-1
PubChem CID154101as HCl: 154100
IUPHAR/BPS7554
DrugBankDB06701 as HCl: DBSALT001458
ChemSpider135807 as HCl: 135806
UNIIM32RH9MFGPas HCl: 1678OK0E08

Trade Name:Focalin® / Attenade®MOA:Norepinephrine-dopamine reuptake inhibitorIndication:Attention deficit hyperactivity disorder (ADHD)Status:ApprovedCompany:Novartis (Originator) , CelgeneSales:$365 Million (Y2015); 
$492 Million (Y2014);
$594 Million (Y2013);
$554 Million (Y2012);
$550 Million (Y2011);ATC Code:N06BA11

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2005-05-26New dosage formFocalin XRAttention deficit hyperactivity disorder (ADHD)Capsule, Extended release5 mg/10 mg/15 mg/20 mg/25 mg/30 mg/35 mg/40 mgNovartis 
2001-11-13Marketing approvalFocalinAttention deficit hyperactivity disorder (ADHD)Tablet2.5 mg/5 mg/10 mgNovartis

Dexmethylphenidate hydrochloride was approved by the U.S. Food and Drug Administration (FDA) on Nov 13, 2001. It was developed and marketed as Focalin® by Novartis in the US.

Dexmethylphenidate hydrochloride is a norepinephrine-dopamine reuptake inhibitor (NDRI). It is indicated for the treatment of attention deficit hyperactivity disorder (ADHD).

Focalin® is available as tablet for oral use, containing 2.5 mg, 5 mg or 10 mg of Dexmethylphenidate hydrochloride. The recommended dose is 10 mg twice daily, at least 4 hours apart.

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NDA 212994, AZSTARYS

FDA APPROVE 2021

Drug Product Name Serdexmethylphenidate and Dexmethylphenidate (SDX/d-MPH)

Dosage Form capsule Strength 26.1/5.2 mg SDX/d-MPH 39.2/7.8 mg SDX/d-MPH 52.3/10.4 mg SDX/d-MPH

Route of Administration oral

Rx/OTC Dispensed Rx

Maximum Daily Dose 52.3 mg serdexmethylphenidate /10.4 mg dmethylphenidate as free base or 56 mg serdexmethylphenidate Chlorid

Dexmethylphenidate, sold under the brand name Focalin among others, is a medication used to treat attention deficit hyperactivity disorder (ADHD) in those over the age of five years.[3] If no benefit is seen after four weeks it is reasonable to discontinue its use.[3] It is taken by mouth.[3] The immediate release formulation lasts up to five hours while the extended release formulation lasts up to twelve hours.[4]

Common side effects include abdominal pain, loss of appetite, and fever.[3] Serious side effects may include abusepsychosissudden cardiac deathmaniaanaphylaxisseizures, and dangerously prolonged erection.[3] Safety during pregnancy and breastfeeding is unclear.[5] Dexmethylphenidate is a central nervous system (CNS) stimulant.[6][3] How it works in ADHD is unclear.[3] It is the more active enantiomer of methylphenidate.[3]

Dexmethylphenidate was approved for medical use in the United States in 2001.[1] It is available as a generic medication.[3] In 2018, it was the 156th most commonly prescribed medication in the United States, with more than 3 million prescriptions.[7][8] It is also available in Switzerland.[9]

SYNRoute 1

Reference:1. US6528530B2.

2. J. Org. Chem. 1998, 63, 9628-9629.Route 2

Reference:1. J. Am. Chem. Soc. 1999, 121,6509-6510.Route 3

Reference:1. Org. Process Res. Dev. 201014, 1473–1475.Route 4

Reference:1. J. Med. Chem. 1998, 41,591-601.Route 5

Reference:1. Org. Lett. 19991, 175-178.

2. Organic Syntheses 198563, 206-212.

Four isomers of methylphenidate are possible, since the molecule has two chiral centers. One pair of threo isomers and one pair of erythro are distinguished, from which primarily d-threo-methylphenidate exhibits the pharmacologically desired effects.[102][124] The erythro diastereomers are pressor amines, a property not shared with the threo diastereomers. When the drug was first introduced it was sold as a 4:1 mixture of erythro:threo diastereomers, but it was later reformulated to contain only the threo diastereomers. “TMP” refers to a threo product that does not contain any erythro diastereomers, i.e. (±)-threo-methylphenidate. Since the threo isomers are energetically favored, it is easy to epimerize out any of the undesired erythro isomers. The drug that contains only dextrorotatory methylphenidate is sometimes called d-TMP, although this name is only rarely used and it is much more commonly referred to as dexmethylphenidate, d-MPH, or d-threo-methylphenidate. A review on the synthesis of enantiomerically pure (2R,2′R)-(+)-threo-methylphenidate hydrochloride has been published.[125]Methylphenidate synthesis

Methylphenidate synthesis graphic

Method 1: Methylphenidate preparation elucidated by Axten et al. (1998)[126] via Bamford-Stevens reaction.

Methylphenidate synthesis graphic

Method 2: Classic methylphenidate synthesis[127]

Methylphenidate synthesis graphic

Method 3: Another synthesis route of methylphenidate which applies Darzens reaction to obtain aldehyde as an intermediate. This route is significant for its selectivity.SYNhttps://onlinelibrary.wiley.com/doi/abs/10.1002/jhet.2705SUN

1.9 Synthesis of (R, R), (R, S), (S, S) and (S, R) methyl 2-piperidin-2-yl-phenylacetate hydrochloride (1a1b1c and 1d)

Compound 8a8b8c or 8d (400 mg, 1.3 mmol) was dissolved into methanol solution (15 mL), and then thionyl chloride (1 mL) was added drop-wise. The reaction mixture was stirred for 12 hours and concentrated in vacuum; a white solid was precipitated and filtered to afford the final product. (1a. 0.28 g, 82% yield; 1b. 0.30 g, 84% yield; 1c. 0.31 g, 85% yield; 1d. 0.30 g, 84% yield). The characterization data of the four final products had been reported [2] by us in 2016.

SYN

https://patents.google.com/patent/US20040180928A1/en

  • Dexmethylphenidate, also known as d-threo-methylphenidate, (R,R)-methylphenidate or (R,R)-α-phenyl-2-piperidineacetic acid methyl ester, having the formula:
  • [0029]
    is CNS (central nervous system) stimulant that is chemically and pharmacologically similar to the amphetamines. Dexmethylphenidate’s CNS actions is milder than those of the amphetamines and have more noticeable effects on mental activities than on motor activities.
  • [0030]
    It has been reported by Sporzny (1961) that among racemic mixtures of threo and erythro diastereomers of methylphenidate, only threo-isomer displays stimulant properties. Dexmethylphenidate hydrochloride (i.e. the d-threo enantiomer of methylphenidate hydrochloride) has been reported to be 5 to 38 times more active than the corresponding (S,S)-methylphenidate hydrochloride (Prashad 2000).
  • [0031]
    A commercially available drug is sold under the name Focalin™ (Novartis) and it consists of dexmethylphenidate in the form of the hydrochloride salt. This product is orally administered and clinically used in the treatment of narcolepsy and as adjunctive treatment in children with attention deficit disorder (ADD) and attention-deficit hyperactivity disorder (ADHD).
  • [0032]
    A synthesis of dexmethylphenidate hydrochloride was firstly described in U.S. Pat. No. 2,838,519 and include resolution of erythro-α-phenyl-2-piperidineacetamide to obtain enantiopure (2R,2′S)-α-phenyl-2-piperidineacetamide, which was subjected to epimerization, hydrolysis, and esterification as shown in Scheme 1:
  • [0033]
    Related example of preparation of dexmethylphenidate from erythro-α-phenyl-2-piperidineacetamide was described in U.S. Pat. No. 5,936,091.
  • [0034]
    Preparation of dexmethylphenidate through optical resolution of threo-α-phenyl-2-piperidineacetamide was described in U.S. Pat. No. 5,965,734, as shown in Scheme 2:
  • [0035]
    Synthetic methods for the preparation of racemic mixture of threo- and erythro-α-phenyl-2-piperidineacetamides as raw materials for the preparation of dexmethylphenidate were described by Panizzon (1944) and Patric (1982) and in U.S. Pat. Nos. 2,507,631, 2,838,519, 2,957,880 and 5,936,091, and in WO 01/27070. These methods include using sodium amide as base in the nucleophilic substitution of chlorine in 2-chloropyridine with phenylacetonitrile followed by hydrolysis of the formed nitrile and reduction of a pyridine ring to a piperidine one by hydrogenation on PtO catalyst, as shown in Scheme 3:
  • [0036]
    Alternatively, 2-bromopyridine was used instead of 2-chloropyridine by Deutsch (1996).
  • [0037]
    In some other methods threo-methylphenidate was used as the raw material for the preparation of dexmethylphenidate. Threo-methylphenidate may be prepared by a several routes, inter alia by the following two processes:
  • [0038]
    i) by esterification of threo-ritalinic acid which may be prepared from erythro-enriched and threo-α-phenyl-2-piperidineacetamides as shown in Scheme 4:
  • [0039]
    ii) by cyclization of easily available 1-(phenylglyoxylyl)piperidine arenesulfonylhydrazone to (R*,R*)-enriched 7-phenyl-1-azabicyclo[4.2.0]octan-8-one and further converting the β-lactam to threo-methylphenidate hydrochloride, as described by Axten (1998), Corey (1965) and Earle (1969) and in WO 99/36403 and shown in Scheme 5:
  • [0040]
    The resolution of threo-methylphenidate to afford dexmethylphenidate was first reported by Patric (1987) which used (R)-(−)-binaphthyl-2,2′-diyl hydrogen phosphate as the resolving agent. Several new resolutions of threo-methylphenidate have been reported recently by Prashad (1999) and in U.S. Pat. Nos. 6,100,401, 6,121,453, 6,162,919 and 6,242,464 as described in Scheme 6:
  • [0041]
    wherein the chiral acid is one of the following: (R)-(−)-binaphthyl-2,2′-diyl hydrogen phosphate, (−)-menthoxyacetic acid, ditoluoyl-D-tartaric acid or dibenzoyl-D-tartaric acid.
  • [0042]
    Resolution of threo-methylphenidate may be also achieved by enzymatic hydrolysis methods as proposed by Prashad (1998) and in WO 98/25902. Such resolution is described in Scheme 7:
  • [0043]
    Resolution of threo-ritalinic acid hydrochloride with (S)-1-phenylethylamine give complex salt (R,R)-enriched threo-ritalinic acid.HCl.(S)-1-phenylethylamine with 77% ee optical purity of ritalinic acid (U.S. Ser. No. 2002/0019535), Scheme 8: 
  • [0119]
  • [0120]
    Gaseous hydrogen chloride was passed through a boiling solution of (R,R)-N-Boc-ritalinic acid (95.4 g, 299 mmol) in methanol (1.5 L). The mixture was stirred for 12 hours under reflux conditions and concentrated to the volume of 250 mL. Toluene (750 mL) was added to the stirred residue, then methanol lo was removed from boiling suspension under normal pressure. The obtained mixture was stirred overnight at 0-5° C. The precipitated solids were filtered off, washed on the filter with toluene (3×50 mL) and dried under reduced pressure to give 78.4 g (97.2% yield) of dexmethylphenidate hydrochloride as white crystals with mp 222-224° C. and [α]D 25 87.0° (c=1, MeOH).
  • [0117]
  • [0118]
    A mixture of crystalline salt of (R,R)-N-Boc-ritalinic acid and (S)-1-phenylamine with [α]D 20 −28.6° (c=1, MeOH) (133.0 g, 302 mmol), ethyl acetate (1.3 L) and solution of citric acid (164.0 g, 845 mmol) in water (1.3 L) was stirred at 15-25° C. for 1.5 hours. The organic layer was separated, washed lo with brine (20 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to give 95.4 g (99%) of (R,R)-N-B
  • [0115]
  • [0116]
    (S)-1-Phenylethylamine (113.8 g, 0.94 mol, 0.6 eq) was added dropwise to a stirred solution of N-Boc-threo-ritalinic acid (500 g, 1.57 mol, 1 eq) in ethyl acetate (5 L) for 1 hour at 20-40° C. The mixture was stirred for 1 hour at 40° C. and overnight at 5° C. The precipitated solids were filtered off, washed on the lo filter with cold ethyl acetate (2×500 mL) and dried under reduced pressure to give 380 g of white crystals with [α]D 20−23.3° (c=1, MeOH). The salt was twice recrystallized from aqueous methanol. The precipitated crystals were filtered off, washed on the filter with cold aqueous methanol and dried under reduced pressure to a constant weight to give 265 g (33.5% yield) of salt of (R,R)-N-Boc-ritalinic acid and (S)
  • [0113]
  • [0114]
    A mixture of solution of N-Boc-threo-ritalinic acid sodium salt (1700 g, 4.98 mmol), citric acid (1150 g, 5.98 mmol) and water (5 mL) was stirred at 15-25° C. for 0.5 hour and extracted with ethyl acetate (3×4 L). Combined organic extracts were washed with brine (2×3 L), dried over sodium sulfate, filtered and evaporated under reduced pressure to constant weight to give 1560 g (98.1% yield) of N-Boc-threo-ritalinic acid with mp 133-134° C. (EtOAc/hexane) and 99.8% purity by HPLC.

Medical uses

Dexmethylphenidate is used as a treatment for ADHD, usually along with psychological, educational, behavioral or other forms of treatment. It is proposed that stimulants help ameliorate the symptoms of ADHD by making it easier for the user to concentrate, avoid distraction, and control behavior. Placebo-controlled trials have shown that once-daily dexmethylphenidate XR was effective and generally well tolerated.[6]

Improvements in ADHD symptoms in children were significantly greater for dexmethylphenidate XR versus placebo.[6] It also showed greater efficacy than osmotic controlled-release oral delivery system (OROS) methylphenidate over the first half of the laboratory classroom day but assessments late in the day favoured OROS methylphenidate.[6]

CLIP

An Improved and Efficient Process for the Production of Highly Pure Dexmethylphenidate Hydrochloride 

Long-Xuan Xing, Cheng-Wu Shen, Yuan-Yuan Sun, Lei Huang, Yong-Yong Zheng,* Jian-Qi Li*

https://onlinelibrary.wiley.com/doi/abs/10.1002/jhet.2705

The present work describes an efficient and commercially viable process for the synthesis of dexmethylphenidate hydrochloride (1), a mild nervous system stimulant. The overall yield is 23% with ~99.9% purity (including seven chemical steps). Formation and control of possible impurities are also described in this report.

An Improved and Efficient Process for the Production of Highly Pure Dexmethylphenidate Hydrochloride - Xing - 2017 - Journal of Heterocyclic Chemistry - Wiley Online Library

(R)-methyl 2-phenyl-2-((R)-piperidin-2-yl)acetate hydrochloride (1). ………… afford 1 as a white solid (107.6 g, 87.3% yield) with 99.50% purity and 99.70% ee. The crude product (107.6 g, 0.4 mol) was further purified by recrystallization from pure water (100 mL) to obtain the qualified product 1 (98.3 g, 91.4% yield) with 99.92 purity and 99.98% ee.

[α] 25 D +85.6 (MeOH, c 1) (lit [4b]. [α] 25 D +84 (MeOH, c 1));

Mp 222-223 C (lit [4b]. Mp 222– 224°C); MS m/z 234 [M + H]+ .

1 H NMR (400Hz, DMSO-d6) δ 1 H NMR (400 MHz, DMSO-d6) δ 9.64 (br, 1H), 8.97 (br, 1H), 7.41-7.26 (m, 5H), 4.18-4.16 (d, J = 9.2Hz, 1H), 3.77-3.75 (m, 1H), 3.66 (s, 3H), 3.25 (m, 1H), 2.94 (m, 1H), 1.67-1.64 (m, 3H), 1.41-1.25 (m, 3H).

13C NMR (100.6 MHz, DMSO-d6) δ 171.3, 134.2, 129.1, 128.6, 128.2, 56.8, 53.3, 52.6, 44.5, 25.7, 21.5, 21.4.

1H-NMR, and 13C-NMR of compound 1………………………………….. 10-11

DEPT,

COSY, NOESY, GHMBC, and HMQC of compound 1……………… 12-14

COSY

NOESY

GHMBC

HMQC

Contraindications

This section is transcluded from Methylphenidate. (edit | history)

Methylphenidate is contraindicated for individuals using monoamine oxidase inhibitors (e.g., phenelzine, and tranylcypromine), or individuals with agitation, ticsglaucoma, or a hypersensitivity to any ingredients contained in methylphenidate pharmaceuticals.[10]

The US Food and Drug Administration (FDA) gives methylphenidate a pregnancy category of C, and women are advised to only use the drug if the benefits outweigh the potential risks.[11] Not enough human studies have been conducted to conclusively demonstrate an effect of methylphenidate on fetal development.[12] In 2018, a review concluded that it has not been teratogenic in rats and rabbits, and that it “is not a major human teratogen”.[13]

Adverse effects

Part of this section is transcluded from Methylphenidate. (edit | history)

Products containing dexmethylphenidate have a side effect profile comparable to those containing methylphenidate.[14]

Addiction experts in psychiatry, chemistry, pharmacology, forensic science, epidemiology, and the police and legal services engaged in delphic analysis regarding 20 popular recreational drugs. Methylphenidate was ranked 13th in dependence, 12th in physical harm, and 18th in social harm.[15]

The most common adverse effects include appetite lossdry mouthanxiety/nervousnessnausea, and insomniaGastrointestinal adverse effects may include abdominal pain and weight lossNervous system adverse effects may include akathisia (agitation/restlessness), irritabilitydyskinesia (tics), lethargy (drowsiness/fatigue), and dizzinessCardiac adverse effects may include palpitations, changes in blood pressure and heart rate (typically mild), and tachycardia (rapid heart rate).[16] Smokers with ADHD who take methylphenidate may increase their nicotine dependence, and smoke more often than before they began using methylphenidate, with increased nicotine cravings and an average increase of 1.3 cigarettes per day.[17] Ophthalmologic adverse effects may include blurred vision and dry eyes, with less frequent reports of diplopia and mydriasis.[18]

There is some evidence of mild reductions in height with prolonged treatment in children.[19] This has been estimated at 1 centimetre (0.4 in) or less per year during the first three years with a total decrease of 3 centimetres (1.2 in) over 10 years.[20][21]

Hypersensitivity (including skin rashurticaria, and fever) is sometimes reported when using transdermal methylphenidate. The Daytrana patch has a much higher rate of skin reactions than oral methylphenidate.[22]

Methylphenidate can worsen psychosis in people who are psychotic, and in very rare cases it has been associated with the emergence of new psychotic symptoms.[23] It should be used with extreme caution in people with bipolar disorder due to the potential induction of mania or hypomania.[24] There have been very rare reports of suicidal ideation, but some authors claim that evidence does not support a link.[19] Logorrhea is occasionally reported. Libido disorders, disorientation, and hallucinations are very rarely reported. Priapism is a very rare adverse event that can be potentially serious.[25]

USFDA-commissioned studies from 2011 indicate that in children, young adults, and adults there is no association between serious adverse cardiovascular events (sudden deathheart attack, and stroke) and the medical use of methylphenidate or other ADHD stimulants.[26]

Because some adverse effects may only emerge during chronic use of methylphenidate, a constant watch for adverse effects is recommended.[27]

A 2018 Cochrane review found that methylphenidate might be associated with serious side effects such as heart problems, psychosis, and death; the certainty of the evidence was stated as very low and the actual risk might be higher.[28]

Overdose

The symptoms of a moderate acute overdose on methylphenidate primarily arise from central nervous system overstimulation; these symptoms include: vomitingnauseaagitationtremorshyperreflexia, muscle twitching, euphoria, confusion, hallucinations, deliriumhyperthermia, sweating, flushing, headache, tachycardiaheart palpitationscardiac arrhythmiashypertensionmydriasis, and dryness of mucous membranes.[29][30] A severe overdose may involve symptoms such as hyperpyrexiasympathomimetic toxidromeconvulsionsparanoiastereotypy (a repetitive movement disorder), rapid muscle breakdowncoma, and circulatory collapse.[29][30][31] A methylphenidate overdose is rarely fatal with appropriate care.[31] Following injection of methylphenidate tablets into an artery, severe toxic reactions involving abscess formation and necrosis have been reported.[32]

Treatment of a methylphenidate overdose typically involves the administration of benzodiazepines, with antipsychoticsα-adrenoceptor agonists and propofol serving as second-line therapies.[31]

Addiction and dependence[edit]

ΔFosB accumulation from excessive drug use 
Top: this depicts the initial effects of high dose exposure to an addictive drug on gene expression in the nucleus accumbens for various Fos family proteins (i.e., c-FosFosBΔFosBFra1, and Fra2).
Bottom: this illustrates the progressive increase in ΔFosB expression in the nucleus accumbens following repeated twice daily drug binges, where these phosphorylated (35–37 kilodalton) ΔFosB isoforms persist in the D1-type medium spiny neurons of the nucleus accumbens for up to 2 months.[33][34]

Methylphenidate is a stimulant with an addiction liability and dependence liability similar to amphetamine. It has moderate liability among addictive drugs;[35][36] accordingly, addiction and psychological dependence are possible and likely when methylphenidate is used at high doses as a recreational drug.[36][37] When used above the medical dose range, stimulants are associated with the development of stimulant psychosis.[38] As with all addictive drugs, the overexpression of ΔFosB in D1-type medium spiny neurons in the nucleus accumbens is implicated in methylphenidate addiction.[37][39]

Methylphenidate has shown some benefits as a replacement therapy for individuals who are addicted to and dependent upon methamphetamine.[40] Methylphenidate and amphetamine have been investigated as a chemical replacement for the treatment of cocaine addiction[41][42][43][44] in the same way that methadone is used as a replacement drug for physical dependence upon heroin. Its effectiveness in treatment of cocaine or psychostimulant addiction, or psychological dependence has not been proven and further research is needed.[45]

Biomolecular mechanisms

Further information: Addiction § Biomolecular mechanisms

Methylphenidate has the potential to induce euphoria due to its pharmacodynamic effect (i.e., dopamine reuptake inhibition) in the brain’s reward system.[39] At therapeutic doses, ADHD stimulants do not sufficiently activate the reward system, or the reward pathway in particular, to the extent necessary to cause persistent increases in ΔFosB gene expression in the D1-type medium spiny neurons of the nucleus accumbens;[36][39][46] consequently, when taken as directed in doses that are commonly prescribed for the treatment of ADHD, methylphenidate use lacks the capacity to cause an addiction.[36][39][46] However, when methylphenidate is used at sufficiently high recreational doses through a bioavailable route of administration (e.g., insufflation or intravenous administration), particularly for use of the drug as a euphoriant, ΔFosB accumulates in the nucleus accumbens.[36][39] Hence, like any other addictive drug, regular recreational use of methylphenidate at high doses eventually gives rise to ΔFosB overexpression in D1-type neurons which subsequently triggers a series of gene transcription-mediated signaling cascades that induce an addiction.[39][46][47]

Overdose

This section is transcluded from Methylphenidate. (edit | history)

The symptoms of a moderate acute overdose on methylphenidate primarily arise from central nervous system overstimulation; these symptoms include: vomitingnauseaagitationtremorshyperreflexia, muscle twitching, euphoria, confusion, hallucinations, deliriumhyperthermia, sweating, flushing, headache, tachycardiaheart palpitationscardiac arrhythmiashypertensionmydriasis, and dryness of mucous membranes.[29][30] A severe overdose may involve symptoms such as hyperpyrexiasympathomimetic toxidromeconvulsionsparanoiastereotypy (a repetitive movement disorder), rapid muscle breakdowncoma, and circulatory collapse.[29][30][31] A methylphenidate overdose is rarely fatal with appropriate care.[31] Following injection of methylphenidate tablets into an artery, severe toxic reactions involving abscess formation and necrosis have been reported.[32]

Treatment of a methylphenidate overdose typically involves the administration of benzodiazepines, with antipsychoticsα-adrenoceptor agonists and propofol serving as second-line therapies.[31]

Interactions

This section is transcluded from Methylphenidate. (edit | history)

Methylphenidate may inhibit the metabolism of vitamin K anticoagulants, certain anticonvulsants, and some antidepressants (tricyclic antidepressants, and selective serotonin reuptake inhibitors). Concomitant administration may require dose adjustments, possibly assisted by monitoring of plasma drug concentrations.[48] There are several case reports of methylphenidate inducing serotonin syndrome with concomitant administration of antidepressants.[49][50][51][52]

When methylphenidate is coingested with ethanol, a metabolite called ethylphenidate is formed via hepatic transesterification,[53][54] not unlike the hepatic formation of cocaethylene from cocaine and ethanol. The reduced potency of ethylphenidate and its minor formation means it does not contribute to the pharmacological profile at therapeutic doses and even in overdose cases ethylphenidate concentrations remain negligible.[55][54]

Coingestion of alcohol (ethanol) also increases the blood plasma levels of d-methylphenidate by up to 40%.[56]

Liver toxicity from methylphenidate is extremely rare, but limited evidence suggests that intake of β-adrenergic agonists with methylphenidate may increase the risk of liver toxicity.[57]

Mode of activity

Methylphenidate is a catecholamine reuptake inhibitor that indirectly increases catecholaminergic neurotransmission by inhibiting the dopamine transporter (DAT) and norepinephrine transporter (NET),[58] which are responsible for clearing catecholamines from the synapse, particularly in the striatum and meso-limbic system.[59] Moreover, it is thought to “increase the release of these monoamines into the extraneuronal space.”[2]

Although four stereoisomers of methylphenidate (MPH) are possible, only the threo diastereoisomers are used in modern practice. There is a high eudysmic ratio between the SS and RR enantiomers of MPH. Dexmethylphenidate (d-threo-methylphenidate) is a preparation of the RR enantiomer of methylphenidate.[60][61] In theory, D-TMP (d-threo-methylphenidate) can be anticipated to be twice the strength of the racemic product.[58][62]

Compd[63]DAT (Ki)DA (IC50)NET (Ki)NE (IC50)
D-TMP1612320639
L-TMP22501600>10K980
DL-TMP1212078851

Pharmacology

Main article: Methylphenidate § Pharmacology

Dexmethylphenidate has a 4–6 hour duration of effect (a long-acting formulation, Focalin XR, which spans 12 hours is also available and has been shown to be as effective as DL (dextro-, levo-)-TMP (threo-methylphenidate) XR (extended release) (Concerta, Ritalin LA), with flexible dosing and good tolerability.[64][65]) It has also been demonstrated to reduce ADHD symptoms in both children[66] and adults.[67] d-MPH has a similar side-effect profile to MPH[14] and can be administered without regard to food intake.[68]

 

References

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  2. Jump up to:a b “Focalin XR- dexmethylphenidate hydrochloride capsule, extended release”DailyMed. 27 June 2020. Retrieved 15 November 2020.
  3. Jump up to:a b c d e f g h i “Dexmethylphenidate Hydrochloride Monograph for Professionals”Drugs.com. American Society of Health-System Pharmacists. Retrieved 15 April 2019.
  4. ^ Mosby’s Drug Reference for Health Professions – E-Book. Elsevier Health Sciences. 2013. p. 455. ISBN 9780323187602.
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  7. ^ “The Top 300 of 2021”ClinCalc. Retrieved 18 February 2021.
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  9. ^ “Focalin XR”Drugs.com. Retrieved 15 April 2019.
  10. ^ “DAYTRANA” (PDF). United States Food and Drug Administration. Noven Pharmaceuticals, Inc. October 2013. Archived (PDF) from the original on 14 July 2014. Retrieved 13 June 2014.
  11. ^ “Methylphenidate: Use During Pregnancy and Breastfeeding”Drugs.com. Archived from the original on 2 January 2018.
  12. ^ Humphreys C, Garcia-Bournissen F, Ito S, Koren G (2007). “Exposure to attention deficit hyperactivity disorder medications during pregnancy”Canadian Family Physician53 (7): 1153–5. PMC 1949295PMID 17872810.
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    • Cooper WO, Habel LA, Sox CM, Chan KA, Arbogast PG, Cheetham TC, Murray KT, Quinn VP, Stein CM, Callahan ST, Fireman BH, Fish FA, Kirshner HS, O’Duffy A, Connell FA, Ray WA (November 2011). “ADHD drugs and serious cardiovascular events in children and young adults”N. Engl. J. Med365 (20): 1896–1904. doi:10.1056/NEJMoa1110212PMC 4943074PMID 22043968.
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    • Habel LA, Cooper WO, Sox CM, Chan KA, Fireman BH, Arbogast PG, Cheetham TC, Quinn VP, Dublin S, Boudreau DM, Andrade SE, Pawloski PA, Raebel MA, Smith DH, Achacoso N, Uratsu C, Go AS, Sidney S, Nguyen-Huynh MN, Ray WA, Selby JV (December 2011). “ADHD medications and risk of serious cardiovascular events in young and middle-aged adults”JAMA306 (24): 2673–2683. doi:10.1001/jama.2011.1830PMC 3350308PMID 22161946.
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  31. Jump up to:a b c d e f Spiller HA, Hays HL, Aleguas A (June 2013). “Overdose of drugs for attention-deficit hyperactivity disorder: clinical presentation, mechanisms of toxicity, and management”. CNS Drugs27 (7): 531–543. doi:10.1007/s40263-013-0084-8PMID 23757186S2CID 40931380The management of amphetamine, dextroamphetamine, and methylphenidate overdose is largely supportive, with a focus on interruption of the sympathomimetic syndrome with judicious use of benzodiazepines. In cases where agitation, delirium, and movement disorders are unresponsive to benzodiazepines, second-line therapies include antipsychotics such as ziprasidone or haloperidol, central alpha-adrenoreceptor agonists such as dexmedetomidine, or propofol. … However, fatalities are rare with appropriate care
  32. Jump up to:a b Bruggisser M, Bodmer M, Liechti ME (2011). “Severe toxicity due to injected but not oral or nasal abuse of methylphenidate tablets”Swiss Med Wkly141: w13267. doi:10.4414/smw.2011.13267PMID 21984207.
  33. ^ Nestler EJ, Barrot M, Self DW (September 2001). “DeltaFosB: a sustained molecular switch for addiction”Proceedings of the National Academy of Sciences of the United States of America98(20): 11042–6. Bibcode:2001PNAS…9811042Ndoi:10.1073/pnas.191352698PMC 58680PMID 11572966Although the ΔFosB signal is relatively long-lived, it is not permanent. ΔFosB degrades gradually and can no longer be detected in brain after 1–2 months of drug withdrawal … Indeed, ΔFosB is the longest-lived adaptation known to occur in adult brain, not only in response to drugs of abuse, but to any other perturbation (that does not involve lesions) as well.
  34. ^ Nestler EJ (December 2012). “Transcriptional mechanisms of drug addiction”Clinical Psychopharmacology and Neuroscience10 (3): 136–43. doi:10.9758/cpn.2012.10.3.136PMC 3569166PMID 23430970The 35–37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. … As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. … ΔFosB overexpression in nucleus accumbens induces NFκB
  35. ^ Morton WA, Stockton GG (2000). “Methylphenidate Abuse and Psychiatric Side Effects”Prim Care Companion J Clin Psychiatry2 (5): 159–164. doi:10.4088/PCC.v02n0502PMC 181133PMID 15014637.
  36. Jump up to:a b c d e Malenka RC, Nestler EJ, Hyman SE (2009). “Chapter 15: Reinforcement and Addictive Disorders”. In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 368. ISBN 9780071481274Cocaine, [amphetamine], and methamphetamine are the major psychostimulants of abuse. The related drug methylphenidate is also abused, although it is far less potent. These drugs elicit similar initial subjective effects ; differences generally reflect the route of administration and other pharmacokinetic factors. Such agents also have important therapeutic uses; cocaine, for example, is used as a local anesthetic (Chapter 2), and amphetamines and methylphenidate are used in low doses to treat attention deficit hyperactivity disorder and in higher doses to treat narcolepsy (Chapter 12). Despite their clinical uses, these drugs are strongly reinforcing, and their long-term use at high doses is linked with potential addiction, especially when they are rapidly administered or when high-potency forms are given.
  37. Jump up to:a b Steiner H, Van Waes V (January 2013). “Addiction-related gene regulation: risks of exposure to cognitive enhancers vs. other psychostimulants”Prog. Neurobiol100: 60–80. doi:10.1016/j.pneurobio.2012.10.001PMC 3525776PMID 23085425.
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  39. Jump up to:a b c d e f Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P (2009). “Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens”Proc. Natl. Acad. Sci. U.S.A106 (8): 2915–20. Bibcode:2009PNAS..106.2915Kdoi:10.1073/pnas.0813179106PMC 2650365PMID 19202072Despite decades of clinical use of methylphenidate for ADHD, concerns have been raised that long-term treatment of children with this medication may result in subsequent drug abuse and addiction. However, meta analysis of available data suggests that treatment of ADHD with stimulant drugs may have a significant protective effect, reducing the risk for addictive substance use (36, 37). Studies with juvenile rats have also indicated that repeated exposure to methylphenidate does not necessarily lead to enhanced drug-seeking behavior in adulthood (38). However, the recent increase of methylphenidate use as a cognitive enhancer by the general public has again raised concerns because of its potential for abuse and addiction (3, 6–10). Thus, although oral administration of clinical doses of methylphenidate is not associated with euphoria or with abuse problems, nontherapeutic use of high doses or i.v. administration may lead to addiction (39, 40).
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  46. Jump up to:a b c Nestler EJ (December 2013). “Cellular basis of memory for addiction”Dialogues in Clinical Neuroscience15 (4): 431–43. doi:10.31887/DCNS.2013.15.4/enestlerPMC 3898681PMID 24459410Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. … A large body of literature has demonstrated that such ΔFosB induction in D1-type NAc neurons increases an animal’s sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement … Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41. … Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.4
  47. ^ Ruffle JK (November 2014). “Molecular neurobiology of addiction: what’s all the (Δ)FosB about?”. The American Journal of Drug and Alcohol Abuse40 (6): 428–37. doi:10.3109/00952990.2014.933840PMID 25083822S2CID 19157711
    The strong correlation between chronic drug exposure and ΔFosB provides novel opportunities for targeted therapies in addiction (118), and suggests methods to analyze their efficacy (119). Over the past two decades, research has progressed from identifying ΔFosB induction to investigating its subsequent action (38). It is likely that ΔFosB research will now progress into a new era – the use of ΔFosB as a biomarker. …
    Conclusions
    ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades, involving effectors such as GluR2 (87,88), Cdk5 (93) and NFkB (100). Moreover, many of these molecular changes identified are now directly linked to the structural, physiological and behavioral changes observed following chronic drug exposure (60,95,97,102). New frontiers of research investigating the molecular roles of ΔFosB have been opened by epigenetic studies, and recent advances have illustrated the role of ΔFosB acting on DNA and histones, truly as a molecular switch(34). As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124). Some of these proposed interventions have limitations (125) or are in their infancy (75). However, it is hoped that some of these preliminary findings may lead to innovative treatments, which are much needed in addiction.

     Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T (2012). “Epigenetic regulation in drug addiction”. Annals of Agricultural and Environmental Medicine19(3): 491–6. PMID 23020045For these reasons, ΔFosB is considered a primary and causative transcription factor in creating new neural connections in the reward centre, prefrontal cortex, and other regions of the limbic system. This is reflected in the increased, stable and long-lasting level of sensitivity to cocaine and other drugs, and tendency to relapse even after long periods of abstinence. These newly constructed networks function very efficiently via new pathways as soon as drugs of abuse are further taken … In this way, the induction of CDK5 gene expression occurs together with suppression of the G9A gene coding for dimethyltransferase acting on the histone H3. A feedback mechanism can be observed in the regulation of these 2 crucial factors that determine the adaptive epigenetic response to cocaine. This depends on ΔFosB inhibiting G9a gene expression, i.e. H3K9me2 synthesis which in turn inhibits transcription factors for ΔFosB. For this reason, the observed hyper-expression of G9a, which ensures high levels of the dimethylated form of histone H3, eliminates the neuronal structural and plasticity effects caused by cocaine by means of this feedback which blocks ΔFosB transcription
     Robison AJ, Nestler EJ (October 2011). “Transcriptional and epigenetic mechanisms of addiction”Nature Reviews. Neuroscience12 (11): 623–37. doi:10.1038/nrn3111PMC 3272277PMID 21989194ΔFosB has been linked directly to several addiction-related behaviors … Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.
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  51. ^ Park YM, Jung YK (May 2010). “Manic switch and serotonin syndrome induced by augmentation of paroxetine with methylphenidate in a patient with major depression”. Progress in Neuro-Psychopharmacology & Biological Psychiatry34 (4): 719–20. doi:10.1016/j.pnpbp.2010.03.016PMID 20298736S2CID 31984813.
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  54. Jump up to:a b Markowitz JS, DeVane CL, Boulton DW, Nahas Z, Risch SC, Diamond F, Patrick KS (2000). “Ethylphenidate formation in human subjects after the administration of a single dose of methylphenidate and ethanol”. Drug Metabolism and Disposition28 (6): 620–4. PMID 10820132.
  55. ^ Markowitz JS, Logan BK, Diamond F, Patrick KS (1999). “Detection of the novel metabolite ethylphenidate after methylphenidate overdose with alcohol coingestion”. Journal of Clinical Psychopharmacology19 (4): 362–6. doi:10.1097/00004714-199908000-00013PMID 10440465.
  56. ^ Patrick KS, Straughn AB, Minhinnett RR, Yeatts SD, Herrin AE, DeVane CL, Malcolm R, Janis GC, Markowitz JS (March 2007). “Influence of ethanol and gender on methylphenidate pharmacokinetics and pharmacodynamics”Clinical Pharmacology and Therapeutics81 (3): 346–53. doi:10.1038/sj.clpt.6100082PMC 3188424PMID 17339864.
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  58. Jump up to:a b Markowitz JS, Patrick KS (June 2008). “Differential pharmacokinetics and pharmacodynamics of methylphenidate enantiomers: does chirality matter?”. Journal of Clinical Psychopharmacology28 (3 Suppl 2): S54-61. doi:10.1097/JCP.0b013e3181733560PMID 18480678.
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External links

Clinical data
Trade namesFocalin, Focalin XR, Attenade, others
Other namesd-threo-methylphenidate (D-TMP)
AHFS/Drugs.comMonograph
MedlinePlusa603014
License dataUS DailyMedDexmethylphenidate
Dependence
liability
Physical: None Psychological: High
Routes of
administration
By mouth
ATC codeN06BA11 (WHO)
Legal status
Legal statusAU: S8 (Controlled drug)CASchedule IIIDEAnlage III (Special prescription form required)UK: Class BUS: Schedule II [1][2]In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability11–52%
Protein binding30%
MetabolismLiver
Elimination half-life4 hours
ExcretionKidney
Identifiers
showIUPAC name
CAS Number40431-64-9 as HCl: 19262-68-1
PubChem CID154101as HCl: 154100
IUPHAR/BPS7554
DrugBankDB06701 as HCl: DBSALT001458
ChemSpider135807 as HCl: 135806
UNIIM32RH9MFGPas HCl: 1678OK0E08
KEGGD07806 as HCl: D03721 
ChEBICHEBI:51860 
ChEMBLChEMBL827 as HCl: ChEMBL904
CompTox Dashboard (EPA)DTXSID70893769 
Chemical and physical data
FormulaC14H19NO2
Molar mass233.311 g·mol−1
3D model (JSmol)Interactive imageas HCl: Interactive image
showSMILES
showInChI

///////////DEXMETHYLPHENIDATE, FDA 2021, APPROVALS 2021

Cl.[H][C@@](C(=O)OC)(C1=CC=CC=C1)[C@@]1([H])CCCCN1

wdt-18

NEW DRUG APPROVALS

ONE TIME

$10.00

Serdexmethylphenidate


Skeletal formula of serdexmethylphenidate
SERDEXMETHYLPHENIDATE CHLORIDE

Serdexmethylphenidate

  • Molecular FormulaC25H30ClN3O8
  • Average mass535.974 Da

CAS

1996626-30-2 

L-Serine, N-[[1-[[[[(2R)-2-[(1R)-2-methoxy-2-oxo-1-phenylethyl]-1-piperidinyl]carbonyl]oxy]methyl]-3-pyridiniumyl]carbonyl]-, chloride (1:1)
N-[(1-{[({(2R)-2-[(1R)-2-Methoxy-2-oxo-1-phenylethyl]-1-piperidinyl}carbonyl)oxy]methyl}-3-pyridiniumyl)carbonyl]-L-serine chloride

Azstarys, FDA APPROVED, 3/2/2021, Products on NDA 212994, Type 1 – New Molecular Entity and Type 4 – New Combination

Serdexmethylphenidate Chloride (SDX), SDX or KP145

Serdexmethylphenidate chloride.png
Molecular FormulaC25H30ClN3O8
SynonymsUNII-FN54BT298YKP415 ClSerdexmethylphenidate chlorideFN54BT298YSerdexmethylphenidate chloride (USAN) 
Molecular Weight536 g/mol

CAS 1996626-30-2

(2S)-3-hydroxy-2-[[1-[[(2R)-2-[(1R)-2-methoxy-2-oxo-1-phenylethyl]piperidine-1-carbonyl]oxymethyl]pyridin-1-ium-3-carbonyl]amino]propanoic acid;chloride

Serdexmethylphenidate is a derivative of dexmethylphenidate created by pharmaceutical company KemPharm. The compound is under investigation for the treatment of ADHD in children, adolescents, and adults as of 2020.[2] The drug was approved for medical use by the FDA in March, 2021. Serdexmethylphenidate is a prodrug which has a delayed onset of action and a prolonged duration of effects compared to dexmethylphenidate, its parent compound.

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Formulations

Serdexmethylphenidate/dexmethylphenidate (Azstarys), a co-formulation of serdexmethylphenidate and dexmethylphenidate, was approved by the Food and Drug Administration (FDA) in March 2021, for the treatment of ADHD in those above six years of age. Co-formulation of serdexmethylphenidate with dexmethylphenidate allows for a more rapid onset of action while still retaining up to 13 hours of therapeutic efficacy.[3][4]

Due to serdexmethylphenidate’s delayed onset and prolonged duration of effects, several dosage forms containing serdexmethylphenidate have been investigated for use as long-acting psychostimulants in the treatment of ADHD. Under the developmental codename KP484, serdexmethylphenidate has been investigated as a “super-extended duration” psychostimulant, with therapeutic efficacy lasting up to 16 hours following oral administration. In 2011, MonoSol Rx entered into a partnership with KenPharm to develop oral films containing KP415.[5]

Abuse potential

The abuse potential of serdexmethylphenidate is theorized to be lower than other psychostimulants because serdexmethylphenidate is an inactive prodrug of dexmethylphenidate, and must undergo enzymatic metabolism prior to exerting any stimulant effects.[6] Common routes of administration used during the abuse of psychostimulants such as insufflation and intravenous injection have little impact on the pharmacokinetics and metabolism of serdexmethylphenidate and do not result in a faster onset of action.[7]

SYN

SYN

US 20200237742

Title(EN) Serdexmethylphenidate Conjugates, Compositions And Methods Of Use Thereof

front page image

Abstract

(EN)

The present technology is directed to one or more compositions comprising serdexmethylphenidate conjugates and unconjugated d-methylphenidate and/or a pharmaceutically acceptable salt thereof. The present technology also relates to one or more compositions and oral formulations comprising serdexmethylphenidate conjugates and unconjugated d-methylphenidate and/or a pharmaceutically acceptable salt thereof. The present technology also relates to one or more methods of using compositions comprising serdexmethylphenidate conjugates and unconjugated d-methylphenidate and/or a pharmaceutically acceptable salt thereof. The present technology additionally relates to one or more pharmaceutical kits containing a composition comprising serdexmethylphenidate conjugates and unconjugated d-methylphenidate and/or a pharmaceutically acceptable salt thereof.

Synthetic Process for Making Serdexmethylphenidate
      1. Synthesis of nicotinoyl-Ser(tBu)-OtBu
      In one embodiment, the nicotinoyl-Ser(tBu)-OtBu precursor is prepared according to Scheme 1.

 (MOL) (CDX)

      2. Synthesis of d-MPH-N-CO 2CH 2—Cl
      In one embodiment, the d-MPH-N-CO 2CH 2—Cl precursor can be prepared according to Scheme 2.

 (MOL) (CDX)

      In an alternate embodiment, d-MPH-N-CO 2CH 2—Cl can be prepared according to Scheme 3.

 (MOL) (CDX)

      3. Preparation of Protected Serdexmethylphenidate
      In one embodiment, the protected serdexmethylphenidate intermediate can be prepared as shown in Scheme 4.

 (MOL) (CDX)

      In an alternate embodiment, the protected serdexmethylphenidate intermediate can be prepared according to Scheme 5.

 (MOL) (CDX)

      4. Deprotection of Protected Serdexmethylphenidate
      In one embodiment, serdexmethylphenidate chloride can be prepared according to Scheme 6.

 (MOL) (CDX)

      In an alternate embodiment, serdexmethylphenidate chloride can be prepared according to Scheme 7.

 (MOL) (CDX)

      Following deprotection (for example, but not limited to, deprotection methods as illustrated by Scheme 6 or Scheme 7) of a protected serdexmethylphenidate intermediate (for example, but not limited to, the serdexmethylphenidate intermediate prepared according to Scheme 4 or Scheme 5) , crude serdexmethylphenidate can be purified by several methods, including, but not limited to, the method according to Scheme 8.

 (MOL) (CDX)

      An alternative embodiment for preparing serdexmethylphenidate is shown in FIG. 1.
      Novel intermediates are produced during the process of synthesizing serdexmethylphenidate (i.e., process intermediates). These process intermediates may be isolated or form in situ, and include, but are not limited to, 3-(((S)-2-(tert-butoxy)-1-carboxyethyl)carbamoyl)-1-((((R)-2-((R)-2-methoxy-2-oxo-1-phenylethyl)piperidine-1-carbonyl)oxy)methyl)pyridin-1-ium; tert-butyl O-(tert-butyl)-N-nicotinoyl-L-serinate; chloromethyl (R)-2-((R)-2-methoxy-2-oxo-1-phenylethyl)piperidine-1-carboxylate; and 3-(((S)-1,3-di-tert-butoxy-1-oxopropan-2-yl)carbamoyl)-1-((((R)-2-((R)-2-methoxy-2-oxo-1-phenylethyl)piperidine-1-carbonyl)oxy)methyl)pyridin-1-ium.
      Novel metabolites and/or novel degradants are produced during the breakdown of serdexmethylphenidate in vitro and/or in vivo. These metabolites and/or degradants include, but are not limited to, 1-((((R)-2-((R)-carboxy(phenyl)methyl)piperidine-1-carbonyl)oxy)methyl)-3-(((S)-1-carboxy-2-hydroxyethyl)carbamoyl)pyridin-1-ium; and 3-carboxy-1-((((R)-2-((R)-2-methoxy-2-oxo-1-phenylethyl)piperidine-1-carbonyl)oxy)methyl)pyridin-1-ium; nicotinic acid (niacin); and nicotinoyl-L-serine.
      In certain embodiments of synthesizing serdexmethylphenidate other compounds may be produced including, but not limited to, dichloromethyl (R)-2-((R)-2-methoxy-2-oxo-1-phenylethyl)piperidine-1-carboxylate; 3-((1-carboxy-2-(((1-((((R)-2-((R)-2-methoxy-2-oxo-1-phenylethyl)piperidine-1-carbonyl)oxy)methyl)pyridin-1-ium-3-carbonyl)-L-seryl)oxy)ethyl)carbamoyl)-1-((((S)-2-((S)-2-methoxy-2-oxo-1-phenylethyl)piperidine-1-carbonyl)oxy)methyl)pyridin-1-ium; N,N-diethyl-N-((((R)-2-((R)-2-methoxy-2-oxo-1-phenylethyl)piperidine-1-carbonyl)oxy)methyl)ethanaminium; 1-((((R)-2-((R)-2-methoxy-2-oxo-1-phenylethyl)piperidine-1-carbonyl)oxy)methyl)-2,6-dimethylpyridin-1-ium; (((S)-1,3-di-tert-butoxy-1-oxopropan-2-yl)amino)methyl (R)-2-((R)-2-methoxy-2-oxo-1-phenylethyl)piperidine-1-carboxylate; ((R)-2-((R)-2-methoxy-2-oxo-1-phenylethyl)piperidin-1-yl)methyl (R)-2-((R)-2-methoxy-2-oxo-1-phenylethyl)piperidine-1-carboxylate; 3-(((R)-1-carboxy-2-chloroethyl)carbamoyl)-1-((((R)-2-((R)-2-methoxy-2-oxo-1-phenylethyl)piperidine-1-carbonyl)oxy)methyl)pyridin-1-ium; and 3-(((S)-3 -hydroxy-1-isopropoxy-1-oxopropan-2-yl)carbamoyl)-1-((((R)-2-((R)-2-methoxy-2-oxo-1-phenylethyl)piperidine-1-carbonyl)oxy)methyl)pyridin-1-ium.

PATENT

US 20190381017

Title(EN) Compositions Comprising Serdexmethylphenidate Conjugates And Methods Of Use Thereof

front page image

Abstract

(EN)

The present technology is directed to one or more compositions comprising serdexmethylphenidate conjugates and unconjugated d-methylphenidate and/or a pharmaceutically acceptable salt thereof. The present technology also relates to one or more compositions and oral formulations comprising serdexmethylphenidate conjugates and unconjugated d-methylphenidate and/or a pharmaceutically acceptable salt thereof. The present technology also relates to one or more methods of using compositions comprising serdexmethylphenidate conjugates and unconjugated d-methylphenidate and/or a pharmaceutically acceptable salt thereof. The present technology additionally relates to one or more pharmaceutical kits containing a composition comprising serdexmethylphenidate conjugates and unconjugated d-methylphenidate and/or a pharmaceutically acceptable salt thereof.

PATENT

WO 2019241019

PAT

WO 2018107131

WO 2018107132

References

  1. ^ “Azstarys Prescribing Information” (PDF). United States Food and Drug Administration. Retrieved 18 March 2021.
  2. ^ “KemPharm’s KP415 and Serdexmethylphenidate (SDX) Prodrug to be Featured in Multiple Sessions at the AACAP 2020 Virtual Meeting”http://www.globenewswire.com.
  3. ^ Mickle T. “Prodrugs for ADHD Treatments: Opportunities & Potential to Fill Unmet Medical Needs” (PDF). Retrieved 15 November 2020.
  4. ^ Eric Bastings, MD (2 March 2021). “NDA 212994 Approval” (PDF). United States Food and Drug Administration. Retrieved 6 March 2021.
  5. ^ Van Arnum P (1 March 2012). “Meeting Solubility Challenges”Pharmaceutical Technology2012 (2): S6–S8. Retrieved 15 November 2020.
  6. ^ Mickle T. “Prodrugs for ADHD Treatments: Opportunities & Potential to Fill Unmet Medical Needs” (PDF). Retrieved 15 November 2020.
  7. ^ Braeckman R (1 October 2018). “Human Abuse Potential of Intravenous Serdexmethylphenidate (SDX), A Novel Prodrug of D-Methylphenidate, in Recreational Stimulant Abusers”Journal of the American Academy of Child & Adolescent Psychiatry57 (10): 176. doi:10.1016/j.jaac.2018.09.141. Retrieved 15 November 2020.

External links

Clinical data
Other namesKP484
License dataUS DailyMedSerdexmethylphenidate
Routes of
administration
By mouth
ATC codeNone
Legal status
Legal statusUS: ℞-only
Pharmacokinetic data
Bioavailability3%[1]
Identifiers
showIUPAC name
CAS Number1996626-30-2 
PubChem CID134823897
ChemSpider81368035
UNIIFN54BT298Y
KEGGD11401
ChEMBLChEMBL4298139
Chemical and physical data
FormulaC25H30ClN3O8
Molar mass535.98 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI
  (verify)

//////////Serdexmethylphenidate, Azstarys, FDA 2021 APPROVALS 2021, SDX, KP 145,

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Sacituzumab govitecan-hziy


TRODELVY structure
Sacituzumab govitecan.png
Sacituzumab govitecan.png
Sacituzumab Govitecan for Metastatic Triple-Negative Breast Cancer -  National Cancer Institute

Sacituzumab govitecan-hziy

1601.8 g/mol

C76H104N12O24S

(2R)-2-amino-3-[1-[[4-[[1-[2-[2-[2-[2-[2-[2-[2-[2-[2-[[2-[2-[[(2S)-6-amino-1-[4-[[(19S)-10,19-diethyl-7-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaen-19-yl]oxycarbonyloxymethyl]anilino]-1-oxohexan-2-yl]amino]-2-oxoethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]triazol-4-yl]methylcarbamoyl]cyclohexyl]methyl]-2,5-dioxopyrrolidin-3-yl]sulfanylpropanoic acid

Trodelvy 

  • hRS 7SN38
  • hRS7-SN38
  • IMMU 132
  • IMMU-132

CAS: 1491917-83-9

M9BYU8XDQ6

EX-A4354

UNII-DA64T2C2IO component ULRUOUDIQPERIJ-PQURJYPBSA-N

UNII-SZB83O1W42 component ULRUOUDIQPERIJ-PQURJYPBSA-N

EfficacyAntineoplastic, Topoisomerase I inhibitor
  DiseaseBreast cancer (triple negative)
sacituzumab govitecan-hziy Archives | Access Market Intelligence

Sacituzumab Govitecan is an antibody drug conjugate containing the humanized monoclonal antibody, hRS7, against tumor-associated calcium signal transducer 2 (TACSTD2 or TROP2) and linked to the active metabolite of irinotecan7-ethyl-10-hydroxycamptothecin (SN-38), with potential antineoplastic activity. The antibody moiety of sacituzumab govitecan selectively binds to TROP2. After internalization and proteolytic cleavage, SN-38 selectively stabilizes topoisomerase I-DNA covalent complexes, resulting in DNA breaks that inhibit DNA replication and trigger apoptosis. TROP2, also known as epithelial glycoprotein-1 (EGP-1), is a transmembrane calcium signal transducer that is overexpressed by a variety of human epithelial carcinomas; this antigen is involved in the regulation of cell-cell adhesion and its expression is associated with increased cancer growth, aggressiveness and metastasis.

wdt-13

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https://www.businesswire.com/news/home/20210407006027/en/FDA-Approves-Trodelvy%C2%AE-the-First-Treatment-for-Metastatic-Triple-Negative-Breast-Cancer-Shown-to-Improve-Progression-Free-Survival-and-Overall-Survival?fbclid=IwAR16bUSCbkK98d8j01NNKVnJ-7r8nHSvCOGE4ogCp_Aex79mNh8AOwQFIQc

FDA Approves Trodelvy®, the First Treatment for Metastatic Triple-Negative Breast Cancer Shown to Improve Progression-Free Survival and Overall Survival

– Trodelvy Significantly Reduced the Risk of Death by 49% Compared with Single-Agent Chemotherapy in the Phase 3 ASCENT Study –

– Trodelvy is Under Regulatory Review in the EU and in the United Kingdom, Canada, Switzerland and Australia as Part of Project Orbis April 07, 2021 07:53 PM Eastern Daylight Time

FOSTER CITY, Calif.–(BUSINESS WIRE)–Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the U.S. Food and Drug Administration (FDA) has granted full approval to Trodelvy® (sacituzumab govitecan-hziy) for adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease. The approval is supported by data from the Phase 3 ASCENT study, in which Trodelvy demonstrated a statistically significant and clinically meaningful 57% reduction in the risk of disease worsening or death (progression-free survival (PFS)), extending median PFS to 4.8 months from 1.7 months with chemotherapy (HR: 0.43; 95% CI: 0.35-0.54; p<0.0001). Trodelvy also extended median overall survival (OS) to 11.8 months vs. 6.9 months (HR: 0.51; 95% CI: 0.41-0.62; p<0.0001), representing a 49% reduction in the risk of death.

Trodelvy is directed to the Trop-2 receptor, a protein frequently expressed in multiple types of epithelial tumors, including TNBC, where high expression is associated with poor survival and relapse. Prior to the FDA approval of Trodelvy, patients with previously treated metastatic TNBC had few treatment options in this high unmet-need setting. The FDA granted accelerated approval to Trodelvy in April 2020 based on objective response rate and duration of response results in a Phase 1/2 study. Today’s approval expands the previous Trodelvy indication to include treatment in adult patients with unresectable locally advanced or metastatic TNBC who have received two or more prior systemic therapies, at least one of them for metastatic disease.

“Women with triple-negative breast cancer have historically had very few effective treatment options and faced a poor prognosis,” said Aditya Bardia, MD, MPH, Director of Breast Cancer Research Program, Mass General Cancer Center and Assistant Professor of Medicine at Harvard Medical School, and global principal investigator of the ASCENT study. “Today’s FDA approval reflects the statistically significant survival benefit seen in the landmark ASCENT study and positions sacituzumab govitecan-hziy as a potential standard of care for pre-treated TNBC.”

“A metastatic TNBC diagnosis is frightening. As an aggressive and difficult-to-treat disease, it’s a significant advance to have an FDA-approved treatment option with a proven survival benefit for patients with metastatic disease that continues to progress,” said Ricki Fairley, Founder and CEO of Touch, the Black Breast Cancer Alliance. “For far too long, people with metastatic TNBC had very few treatment options. Today’s news continues the progress of bringing more options to treat this devastating disease.”

Among all patients evaluable for safety in the ASCENT study (n=482), Trodelvy had a safety profile consistent with the previously approved FDA label. The most frequent Grade ≥3 adverse reactions for Trodelvy compared to single-agent chemotherapy were neutropenia (52% vs. 34%), diarrhea (11% vs. 1%), leukopenia (11% vs. 6%) and anemia (9% vs. 6%). Adverse reactions leading to treatment discontinuation occurred in 5% of patients receiving Trodelvy.

“Today’s approval is the culmination of a multi-year development program and validates the clinical benefit of this important treatment in metastatic TNBC,” said Merdad Parsey, MD, PhD, Chief Medical Officer, Gilead Sciences. “Building upon this milestone, we are committed to advancing Trodelvy with worldwide regulatory authorities so that, pending their decision, Trodelvy may become available to many more people around the world who are facing this difficult-to-treat cancer.”

Regulatory submissions for Trodelvy in metastatic TNBC have been filed in the United Kingdom, Canada, Switzerland and Australia as part of Project Orbis, an initiative of the FDA Oncology Center of Excellence (OCE) that provides a framework for concurrent submission and review of oncology products among international partners, as well as in Singapore through our partner Everest Medicines.The European Medicines Agency has also validated a Marketing Authorization Application for Trodelvy in the European Union. All filings are based on data from the Phase 3 ASCENT study.

Trodelvy Boxed Warning

The Trodelvy U.S. Prescribing Information has a BOXED WARNING for severe or life-threatening neutropenia and severe diarrhea; see below for Important Safety Information.

About Trodelvy

Trodelvy (sacituzumab govitecan-hziy) is a first-in-class antibody and topoisomerase inhibitor conjugate directed to the Trop-2 receptor, a protein frequently expressed in multiple types of epithelial tumors, including metastatic triple-negative breast cancer (TNBC), where high expression is associated with poor survival and relapse.

Trodelvy is also being developed as an investigational treatment for metastatic urothelial cancer, hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER 2-) metastatic breast cancer and metastatic non-small cell lung cancer. Additional evaluation across multiple solid tumors is also underway.

About Triple-Negative Breast Cancer (TNBC)

TNBC is an aggressive type of breast cancer, accounting for approximately 15% of all breast cancers. The disease is diagnosed more frequently in younger and premenopausal women and is more prevalent in African American and Hispanic women. TNBC cells do not have estrogen and progesterone receptors and have limited HER 2. Medicines targeting these receptors therefore are not typically effective in treating TNBC.

About the ASCENT Study

The Phase 3 ASCENT study, an open-label, active-controlled, randomized confirmatory trial, enrolled more than 500 patients with relapsed/refractory metastatic triple-negative breast cancer (TNBC) who had received two or more prior systemic therapies (including a taxane), at least one of them for metastatic disease. Patients were randomized to receive either Trodelvy or a chemotherapy chosen by the patients’ treating physicians. The primary efficacy outcome was progression-free survival (PFS) in patients without brain metastases at baseline, as measured by a blinded, independent, centralized review using RECIST v1.1 criteria. Additional efficacy measures included PFS for the full population (all patients with and without brain metastases) and overall survival (OS). More information about ASCENT is available at http://clinicaltrials.gov/show/NCT02574455.

Important Safety Information for Trodelvy

BOXED WARNING: NEUTROPENIA AND DIARRHEA

  • Severe, life-threatening, or fatal neutropenia may occur. Withhold TRODELVY for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment. Consider G-CSF for secondary prophylaxis. Initiate anti-infective treatment in patient with febrile neutropenia without delay.
  • Severe diarrhea may occur. Monitor patients with diarrhea and give fluid and electrolytes as needed. Administer atropine, if not contraindicated, for early diarrhea of any severity. At the onset of late diarrhea, evaluate for infectious causes and, if negative, promptly initiate loperamide. If severe diarrhea occurs, withhold TRODELVY until resolved to ≤ Grade 1 and reduce subsequent doses.

CONTRAINDICATIONS

  • Severe hypersensitivity to TRODELVY

WARNINGS AND PRECAUTIONS

Neutropenia: Dose modifications may be required due to neutropenia. Neutropenia occurred in 62% of patients treated with TRODELVY, leading to permanent discontinuation in 0.5% of patients. Grade 3-4 neutropenia occurred in 47% of patients. Febrile neutropenia occurred in 6%.

Diarrhea: Diarrhea occurred in 64% of all patients treated with TRODELVY. Grade 3 diarrhea occurred in 12% of patients. Neutropenic colitis occurred in 0.5% of patients. Withhold TRODELVY for Grade 3-4 diarrhea and resume when resolved to ≤ Grade 1. At onset, evaluate for infectious causes and if negative, promptly initiate loperamide, 4 mg initially followed by 2 mg with every episode of diarrhea for a maximum of 16 mg daily. Discontinue loperamide 12 hours after diarrhea resolves. Additional supportive measures (e.g., fluid and electrolyte substitution) may also be employed as clinically indicated. Patients who exhibit an excessive cholinergic response to treatment can receive appropriate premedication (e.g., atropine) for subsequent treatments.

Hypersensitivity and Infusion-Related Reactions: TRODELVY can cause severe and life-threatening hypersensitivity and infusion-related reactions, including anaphylactic reactions. Hypersensitivity reactions within 24 hours of dosing occurred in 37% of patients. Grade 3-4 hypersensitivity occurred in 1% of patients. The incidence of hypersensitivity reactions leading to permanent discontinuation of TRODELVY was 0.4%. Pre-infusion medication is recommendedObserve patients closely for hypersensitivity and infusion-related reactions during each infusion and for at least 30 minutes after completion of each infusion. Medication to treat such reactions, as well as emergency equipment, should be available for immediate use.

Nausea and Vomiting: Nausea occurred in 67% of all patients treated with TRODELVY. Grade 3-4 nausea occurred in 5% of patients. Vomiting occurred in 40% of patients and Grade 3-4 vomiting occurred in 3% of these patients. Premedicate with a two or three drug combination regimen (e.g., dexamethasone with either a 5-HT3 receptor antagonist or an NK-1 receptor antagonist as well as other drugs as indicated) for prevention of chemotherapy-induced nausea and vomiting (CINV). Withhold TRODELVY doses for Grade 3 nausea or Grade 3-4 vomiting and resume with additional supportive measures when resolved to Grade ≤ 1. Additional antiemetics and other supportive measures may also be employed as clinically indicated. All patients should be given take-home medications with clear instructions for prevention and treatment of nausea and vomiting.

Increased Risk of Adverse Reactions in Patients with Reduced UGT1A1 Activity: Individuals who are homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at increased risk for neutropenia, febrile neutropenia, and anemia and may be at increased risk for other adverse reactions with TRODELVY. The incidence of Grade 3-4 neutropenia in genotyped patients was 69% in patients homozygous for the UGT1A1*28, 48% in patients heterozygous for the UGT1A1*28 allele and 46% in patients homozygous for the wild-type allele. The incidence of Grade 3-4 anemia in genotyped patients was 24% in patients homozygous for the UGT1A1*28 allele, 8% in patients heterozygous for the UGT1A1*28 allele, and 10% in patients homozygous for the wild-type allele. Closely monitor patients with known reduced UGT1A1 activity for adverse reactions. Withhold or permanently discontinue TRODELVY based on severity of the observed adverse reactions in patients with evidence of acute early-onset or unusually severe adverse reactions, which may indicate reduced UGT1A1 function.

Embryo-Fetal Toxicity: Based on its mechanism of action, TRODELVY can cause teratogenicity and/or embryo-fetal lethality when administered to a pregnant woman. TRODELVY contains a genotoxic component, SN-38, and targets rapidly dividing cells. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TRODELVY and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TRODELVY and for 3 months after the last dose.

ADVERSE REACTIONS

In the ASCENT study (IMMU-132-05), the most common adverse reactions (incidence ≥25%) were nausea, neutropenia, diarrhea, fatigue, alopecia, anemia, vomiting, constipation, rash, decreased appetite, and abdominal pain. The most frequent serious adverse reactions (SAR) (>1%) were neutropenia (7%), diarrhea (4%), and pneumonia (3%). SAR were reported in 27% of patients, and 5% discontinued therapy due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence ≥25%) in the ASCENT study were reduced hemoglobin, lymphocytes, leukocytes, and neutrophils.

DRUG INTERACTIONS

UGT1A1 Inhibitors: Concomitant administration of TRODELVY with inhibitors of UGT1A1 may increase the incidence of adverse reactions due to potential increase in systemic exposure to SN-38. Avoid administering UGT1A1 inhibitors with TRODELVY.

UGT1A1 Inducers: Exposure to SN-38 may be substantially reduced in patients concomitantly receiving UGT1A1 enzyme inducers. Avoid administering UGT1A1 inducers with TRODELVY

Please see full Prescribing Information, including BOXED WARNING.

About Gilead Sciences

Gilead Sciences, Inc. is a biopharmaceutical company that has pursued and achieved breakthroughs in medicine for more than three decades, with the goal of creating a healthier world for all people. The company is committed to advancing innovative medicines to prevent and treat life-threatening diseases, including HIV, viral hepatitis and cancer. Gilead operates in more than 35 countries worldwide, with headquarters in Foster City, California.

Sacituzumab govitecan, sold under the brand name Trodelvy, is a Trop-2-directed antibody and topoisomerase inhibitor drug conjugate indicated for the treatment of metastatic triple-negative breast cancer (mTNBC) in adult patients that have received at least two prior therapies.[1][2]

The most common side effects are nauseaneutropeniadiarrheafatigueanemiavomitingalopecia (hair loss), constipationdecreased appetiterash and abdominal pain.[1][2] Sacituzumab govitecan has a boxed warning about the risk of severe neutropenia (abnormally low levels of white blood cells) and severe diarrhea.[1][2] Sacituzumab govitecan may cause harm to a developing fetus or newborn baby.[1] Women are advised not to breastfeed while on sacituzumab govitecan and 1 month after the last dose is administered.[3]

The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.[4]

Mechanism

Sacituzumab govitecan is a conjugate of the humanized anti-Trop-2 monoclonal antibody linked with SN-38, the active metabolite of irinotecan.[5] Each antibody having on average 7.6 molecules of SN-38 attached.[6] SN-38 is too toxic to administer directly to patients, but linkage to an antibody allows the drug to specifically target cells containing Trop-2.

Sacituzumab govitecan is a Trop-2-directed antibody and topoisomerase inhibitor drug conjugate, meaning that the drug targets the Trop-2 receptor that helps the cancer grow, divide and spread, and is linked to topoisomerase inhibitor, which is a chemical compound that is toxic to cancer cells.[1] Approximately two of every ten breast cancer diagnoses worldwide are triple-negative.[1] Triple-negative breast cancer is a type of breast cancer that tests negative for estrogen receptors, progesterone receptors and human epidermal growth factor receptor 2 (HER2) protein.[1] Therefore, triple-negative breast cancer does not respond to hormonal therapy medicines or medicines that target HER2.[1]

Development

Immunomedics announced in 2013, that it had received fast track designation from the US Food and Drug Administration (FDA) for the compound as a potential treatment for non-small cell lung cancer, small cell lung cancer, and metastatic triple-negative breast cancer. Orphan drug status was granted for small cell lung cancer and pancreatic cancer.[7][8] In February 2016, Immunomedics announced that sacituzumab govitecan had received an FDA breakthrough therapy designation (a classification designed to expedite the development and review of drugs that are intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition) for the treatment of patients with triple-negative breast cancer who have failed at least two other prior therapies for metastatic disease.[9][10]

History

Sacituzumab govitecan was added to the proposed INN list in 2015,[11] and to the recommended list in 2016.[12]

Sacituzumab govitecan-hziy was approved for use in the United States in April 2020.[1][13][14][2]

Sacituzumab govitecan-hziy was approved based on the results of IMMU-132-01, a multicenter, single-arm clinical trial (NCT01631552) of 108 subjects with metastatic triple-negative breast cancer who had received at least two prior treatments for metastatic disease.[1][14][2] Of the 108 patients involved within the study, 107 were female and 1 was male.[15] Subjects received sacituzumab govitecan-hziy at a dose of 10 milligrams per kilogram of body weight intravenously on days one and eight every 21 days.[14][15] Treatment with sacituzumab govitecan-hziy was continued until disease progression or unacceptable toxicity.[15] Tumor imaging was obtained every eight weeks.[14][2] The efficacy of sacituzumab govitecan-hziy was based on the overall response rate (ORR) – which reflects the percentage of subjects that had a certain amount of tumor shrinkage.[1][14] The ORR was 33.3% (95% confidence interval [CI], 24.6 to 43.1). [1][14][15] Additionally, with the 33.3% of study participants who achieved a response, 2.8% of patients experienced complete responses.[15] The median time to response in patients was 2.0 months (range, 1.6 to 13.5), the median duration of response was 7.7 months (95% confidence interval [CI], 4.9 to 10.8), the median progression free survival was 5.5 months, and the median overall survival was 13.0 months.[15] Of the subjects that achieved an objective response to sacituzumab govitecan-hziy, 55.6% maintained their response for six or more months and 16.7% maintained their response for twelve or more months.[1][14]

Sacituzumab govitecan-hziy was granted accelerated approval along with priority reviewbreakthrough therapy, and fast track designations.[1][14] The U.S. Food and Drug Administration (FDA) granted approval of Trodelvy to Immunomedics, Inc.[1]

References

  1. Jump up to:a b c d e f g h i j k l m n o “FDA Approves New Therapy for Triple Negative Breast Cancer That Has Spread, Not Responded to Other Treatments”U.S. Food and Drug Administration (FDA). 22 April 2020. Retrieved 22 April 2020.  This article incorporates text from this source, which is in the public domain.
  2. Jump up to:a b c d e f “Drug Trial Snapshot: Trodelvy”U.S. Food and Drug Administration (FDA). 22 April 2020. Retrieved 29 April 2020. This article incorporates text from this source, which is in the public domain.
  3. ^ (PDF)https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761115s000lbl.pdf. Missing or empty |title= (help)
  4. ^ “New Drug Therapy Approvals 2020”U.S. Food and Drug Administration (FDA). 31 December 2020. Retrieved 17 January2021.  This article incorporates text from this source, which is in the public domain.
  5. ^ Sacituzumab Govitecan (IMMU-132), an Anti-Trop-2/SN-38 Antibody-Drug Conjugate: Characterization and Efficacy in Pancreatic, Gastric, and Other Cancers. 2015
  6. ^ “Novel Agents are Targeting Drivers of TNBC”http://www.medpagetoday.com. 28 June 2016.
  7. ^ “Sacituzumab govitecan Orphan Drug Designation and Approval”U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 22 April 2020.
  8. ^ “Sacituzumab govitecan Orphan Drug Designation and Approval”U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 22 April 2020.
  9. ^ “New Therapy Shows Early Promise, Continues to Progress in Triple-Negative Breast Cancer”Cure Today.
  10. ^ “U.S. Food and Drug Administration (FDA) Grants Breakthrough Therapy Designation to Immunomedics for Sacituzumab Govitecan for the Treatment of Patients With Triple-Negative Breast Cancer”(Press release). Immunomedics. 5 February 2016. Retrieved 25 April 2020 – via GlobeNewswire.
  11. ^ World Health Organization (2015). “International nonproprietary names for pharmaceutical substances (INN): proposed INN: list 113”. WHO Drug Information29 (2): 260–1. hdl:10665/331080.
  12. ^ World Health Organization (2016). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 75”. WHO Drug Information30 (1): 151–3. hdl:10665/331046.
  13. ^ “Trodelvy: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 22 April 2020.
  14. Jump up to:a b c d e f g h “FDA grants accelerated approval to sacituzumab govitecan-hziy for metastatic triple negative breast cancer”U.S. Food and Drug Administration (FDA). 22 April 2020. Retrieved 23 April 2020.  This article incorporates text from this source, which is in the public domain.
  15. Jump up to:a b c d e f “Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer”The New England Journal of Medicine.

Further reading

External links

 
Monoclonal antibody
Type?
SourceHumanized (from mouse)
TargetTrop-2
Clinical data
Trade namesTrodelvy
Other namesIMMU-132, hRS7-SN-38, sacituzumab govitecan-hziy
AHFS/Drugs.comMonograph
MedlinePlusa620034
License dataUS DailyMedSacituzumab_govitecan
Pregnancy
category
Contraindicated
ATC codeNone
Legal status
Legal statusUS: ℞-only
Identifiers
CAS Number1491917-83-9
PubChem CID91668186
DrugBankDB12893
ChemSpidernone
UNIIM9BYU8XDQ6
KEGGD10985
Chemical and physical data
FormulaC76H104N12O24S
Molar mass1601.79 g·mol−1
3D model (JSmol)Interactive image
showSMILES
show 

//////////sacituzumab govitecan-hziy, fda 2021, approvals 2021, Trodelvy , hRS 7SN38, hRS7-SN38, IMMU 132, IMMU-132, MONOCLONAL ANTIBODY, Sacituzumab govitecan, sacituzumab govitecan-hziy, CANCER, MONOCLONAL ANTIBODIES

#sacituzumab govitecan-hziy, #fda 2021, #approvals 2021, #Trodelvy , #hRS 7SN38, #hRS7-SN38, #IMMU 132, #IMMU-132, #MONOCLONAL ANTIBODY, #Sacituzumab govitecan, #sacituzumab govitecan-hziy, #CANCER, #MONOCLONAL ANTIBODIES

CCC1=C2CN3C(=CC4=C(C3=O)COC(=O)C4(CC)OC(=O)OCC5=CC=C(C=C5)NC(=O)C(CCCCN)NC(=O)COCC(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCN6C=C(N=N6)CNC(=O)C7CCC(CC7)CN8C(=O)CC(C8=O)SCC(C(=O)O)N)C2=NC9=C1C=C(C=C9)O

wdt-14

NEW DRUG APPROVALS

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Dasiglucagon


Dasiglucagon.png
2D chemical structure of 1544300-84-6
str1

Dasiglucagon

Treatment of Hypoglycemia in Type 1 and Type 2 Diabetes Patients

FormulaC152H222N38O50
CAS1544300-84-6
Mol weight3381.6137

FDA APPROVED,  2021/3/22, Zegalogue

Zealand Pharma A/S

UNIIAD4J2O47FQ

HypoPal rescue pen

SVG Image
IUPAC CondensedH-His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Aib-Ala-Arg-Ala-Glu-Glu-Phe-Val-Lys-Trp-Leu-Glu-Ser-Thr-OH
SequenceHSQGTFTSDYSKYLDXARAEEFVKWLEST
HELMPEPTIDE1{H.S.Q.G.T.F.T.S.D.Y.S.K.Y.L.D.[Aib].A.R.A.E.E.F.V.K.W.L.E.S.T}$$$$
IUPACL-histidyl-L-seryl-L-glutaminyl-glycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-alpha-aspartyl-L-tyrosyl-L-seryl-L-lysyl-L-tyrosyl-L-leucyl-L-alpha-aspartyl-alpha-methyl-alanyl-L-alanyl-L-arginyl-L-alanyl-L-alpha-glutamyl-L-alpha-glutamyl-L-phenylalanyl-L-valyl-L-lysyl-L-tryptophyl-L-leucyl-L-alpha-glutamyl-L-seryl-L-threonine

(4S)-4-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3R)-2-[[2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-amino-3-(1H-imidazol-4-yl)propanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]acetyl]amino]-3-hydroxybutanoyl]amino]-3-phenylpropanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-hydroxypropanoyl]amino]hexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-3-carboxypropanoyl]amino]-2-methylpropanoyl]amino]propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-4-carboxy-1-[[(2S)-1-[[(1S,2R)-1-carboxy-2-hydroxypropyl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-5-oxopentanoic acid

. [16-(2-methylalanine)(S>X),17-L-alanine(R>A),20-L-α-glutamyl(Q>E),21-L-αglutamyl(D>E),24-L-lysyl(Q>K),27-L-α-glutamyl(M>E),28-L-serine(N>S)]human glucagon

L-Threonine, L-histidyl-L-seryl-L-glutaminylglycyl-L-threonyl-L- phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl-L-tyrosyl-L-seryl-L- lysyl-L-tyrosyl-L-leucyl-L-α-aspartyl-2-methylalanyl-L-alanyl-L- arginyl-L-alanyl-L-α-glutamyl-L-α-glutamyl-L-phenylalanyl-L- valyl-L-lysyl-L-tryptophyl-L-leucyl-L-α-glutamyl-L-seryl

ZP-4207

His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-aib-Ala-Arg-Ala-Glu-Glu-Phe-Val-Lys-Trp-Leu-Glu-Ser-Thr

L-Threonine, L-histidyl-L-seryl-L-glutaminylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-alpha-aspartyl-L-tyrosyl-L-seryl-L-lysyl-L-tyrosyl-L-leucyl-L-alpha-aspartyl-2-methylalanyl-L-alanyl-L-arginyl-L-alanyl-L-alpha-glutamyl-L-alphaC152 H222 N38 O50L-Threonine, L-histidyl-L-seryl-L-glutaminylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl-L-tyrosyl-L-seryl-L-lysyl-L-tyrosyl-L-leucyl-L-α-aspartyl-2-methylalanyl-L-alanyl-L-arginyl-L-alanyl-L-α-glutamyl-L-α-glutamyl-L-phenylalanyl-L-valyl-L-lysyl-L-tryptophyl-L-leucyl-L-α-glutamyl-L-seryl-Molecular Weight3381.61

Other Names

  • L-Histidyl-L-seryl-L-glutaminylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl-L-tyrosyl-L-seryl-L-lysyl-L-tyrosyl-L-leucyl-L-α-aspartyl-2-methylalanyl-L-alanyl-L-arginyl-L-alanyl-L-α-glutamyl-L-α-glutamyl-L-phenylalanyl-L-valyl-L-lysyl-L-tryptophyl-L-leucyl-L-α-glutamyl-L-seryl-L-threonine
  • Developer Beta Bionics; Zealand Pharma
  • ClassAntihyperglycaemics; Antihypoglycaemics; Peptides
  • Mechanism of ActionGlucagon receptor agonists
  • Orphan Drug StatusYes – Hypoglycaemia; Congenital hyperinsulinism
  • RegisteredHypoglycaemia
  • Phase IIICongenital hyperinsulinism
  • Phase II/IIIType 1 diabetes mellitus
  • 22 Mar 2021Registered for Hypoglycaemia (In children, In adolescents, In adults, In the elderly) in USA (SC) – First global approval
  • 22 Mar 2021Zealand Pharma anticipates the launch of dasiglucagon in USA (SC, Injection) in June 2021
  • 22 Mar 2021Pooled efficacy and safety data from three phase III trials in Hypoglycaemia released by Zealand Pharma

NEW DRUG APPROVALS

one time

$10.00

PATENTS

WO 2014016300

US 20150210744

PAPER

Pharmaceutical Research (2018), 35(12), 1-13

Dasiglucagon, sold under the brand name Zegalogue, is a medication used to treat severe hypoglycemia in people with diabetes.[1]

The most common side effects include nausea, vomiting, headache, diarrhea, and injection site pain.[1]

Dasiglucagon was approved for medical use in the United States in March 2021.[1][2][3] It was designated an orphan drug in August 2017.[4]

Dasiglucagon is under investigation in clinical trial NCT03735225 (Evaluation of the Safety, Tolerability and Bioavailability of Dasiglucagon Following Subcutaneous (SC) Compared to IV Administration).

Medical uses

Dasiglucagon is indicated for the treatment of severe hypoglycemia in people aged six years of age and older with diabetes.[1][2]

Contraindications

Dasiglucagon is contraindicated in people with pheochromocytoma or insulinoma.[1]

References

  1. Jump up to:a b c d e f https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214231s000lbl.pdf
  2. Jump up to:a b “Dasiglucagon: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 22 March 2021.
  3. ^ “Zealand Pharma Announces FDA Approval of Zegalogue (dasiglucagon) injection, for the Treatment of Severe Hypoglycemia in People with Diabetes” (Press release). Zealand Pharma. 22 March 2021. Retrieved 22 March 2021 – via GlobeNewswire.
  4. ^ “Dasiglucagon Orphan Drug Designations and Approvals”U.S. Food and Drug Administration (FDA). 10 August 2017. Retrieved 22 March 2021.

External links

  • “Dasiglucagon”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT03378635 for “A Trial to Confirm the Efficacy and Safety of Dasiglucagon in the Treatment of Hypoglycemia in Type 1 Diabetes Subjects” at ClinicalTrials.gov
  • Clinical trial number NCT03688711 for “Trial to Confirm the Clinical Efficacy and Safety of Dasiglucagon in the Treatment of Hypoglycemia in Subjects With T1DM” at ClinicalTrials.gov
  • Clinical trial number NCT03667053 for “Trial to Confirm the Efficacy and Safety of Dasiglucagon in the Treatment of Hypoglycemia in T1DM Children” at ClinicalTrials.gov
Clinical data
Trade namesZegalogue
AHFS/Drugs.comZegalogue
License dataUS DailyMedDasiglucagon
Routes of
administration
Subcutaneous
Drug classGlucagon receptor agonist
ATC codeNone
Legal status
Legal statusUS: ℞-only [1]
Identifiers
showIUPAC name
CAS Number1544300-84-6
PubChem CID126961379
DrugBankDB15226
UNIIAD4J2O47FQ
KEGGD11359
Chemical and physical data
FormulaC152H222N38O50
Molar mass3381.664 g·mol−1
3D model (JSmol)Interactive image

///////////Dasiglucagon, FDA 2021,  APPROVALS 2021, Zegalogue, ダシグルカゴン, ZP 4207, ZP-GA-1 Hypoglycemia, Type 1, Type 2 , Diabetes Patients, Zealand Pharma A/S, Orphan Drug Status,  Hypoglycaemia, Congenital hyperinsulinism,  HypoPal rescue pen, DIABETES

#Dasiglucagon, #FDA 2021,  #APPROVALS 2021, #Zegalogue, #ダシグルカゴン, #ZP 4207, ZP-GA-1 #Hypoglycemia, #Type 1, #Type 2 , #Diabetes Patients, #Zealand Pharma A/S, #Orphan Drug Status,  #Hypoglycaemia, #Congenital hyperinsulinism,  #HypoPal rescue pen, #DIABETESSMILES

  • C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)NC(C)(C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC4=CC=CC=C4)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC5=CNC6=CC=CC=C65)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CO)NC(=O)[C@H](CC7=CNC=N7)N)O

Lisocabtagene maraleucel


U.S. FDA Accepts Priority Review for Lisocabtagene Maraleucel R/R Large B-Cell Lymphoma - Onco'ZineLisocabtagene maraleucel (liso-cel; JCAR017; Anti-CD19 CAR T-Cells) is an investigational chimeric antigen receptor (CAR) T-cell therapy designed to target CD19, [1][2] which is a surface glycoprotein expressed during normal B-cell development and maintained following malignant transformation of B cells. [3][4][5] Liso-cel CAR T-cells aim to target and CD-19 expressing cells through a CAR construct that includes an anti-CD19 single-chain variable fragment (scFv) targeting domain for antigen specificity, a transmembrane domain, a 4-1BB costimulatory domain hypothesized to increase T-cell proliferation and persistence, and a CD3-zeta T-cell activation domain. [1][2][6][7][8][9] The defined composition of liso-cel may limit product variability; however, the clinical significance of defined composition is unknown. [1][10] Image Courtesy: 2019/2020 Celgene/Juno Therapeutics / Bristol Meyers Squibb.

REF https://www.oncozine.com/u-s-fda-accepts-priority-review-for-lisocabtagene-maraleucel-r-r-large-b-cell-lymphoma/

Lisocabtagene maraleucel

リソカブタゲンマラルユーセル;

JCAR 017

STN# BLA 125714

  • Adoptive immunotherapy agent JCAR 017
  • Autologous anti-CD19 scFv/4-1BB/CD3ζ/CD28 chimeric antigen receptor-expressing CD4+/CD8+ central memory T cell JCAR 017
  • CAR T-cell JCAR 017

FDA 2021, 2021/2/24, BREYANZI

Juno Therapeutics

Antineoplastic, Anti-CD19 CAR-T cell

An immunotherapeutic autologous T cell preparation expressing a chimeric antigen receptor (CAR) specific to the CD19 antigen (Juno Therapeutics, Inc., Seattle, Washington, USA – FDA Clinical Trial Data)

  • For the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.

Lisocabtagene maraleucel, sold under the brand name Breyanzi, is a cell-based gene therapy used to treat large B-cell lymphoma.[1][3]

Side effects of lisocabtagene maraleucel include hypersensitivity reactions, serious infections, low blood cell counts and a weakened immune system.[3]

Lisocabtagene maraleucel, a chimeric antigen receptor (CAR) T cell therapy, is the third gene therapy approved by the U.S. Food and Drug Administration (FDA) for certain types of non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL).[3] Lisocabtagene maraleucel was approved for medical use in the United States in February 2021.[1][3]

U.S. Food and Drug Administration Approves Bristol Myers Squibb's Breyanzi (lisocabtagene maraleucel), a New CAR T Cell Therapy for Adults with Relapsed or Refractory Large B-cell Lymphoma | Business Wire

Medical uses

Lisocabtagene maraleucel is indicated for the treatment of adults with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.[1][3]

Lisocabtagene maraleucel is not indicated for the treatment of people with primary central nervous system lymphoma.[3]

Adverse effects

The labeling carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T cells, causing high fever and flu-like symptoms and neurologic toxicities.[3]

History

The safety and efficacy of lisocabtagene maraleucel were established in a multicenter clinical trial of more than 250 adults with refractory or relapsed large B-cell lymphoma.[3] The complete remission rate after treatment with lisocabtagene maraleucel was 54%.[3]

The FDA granted lisocabtagene maraleucel orphan drugregenerative medicine advanced therapy (RMAT) and breakthrough therapy designations.[3] Lisocabtagene maraleucel is the first regenerative medicine therapy with RMAT designation to be licensed by the FDA.[3] The FDA granted approval of Breyanzi to Juno Therapeutics Inc., a Bristol-Myers Squibb Company.[3]

SYN

WO 2018156680

WO 2018183366

Saishin Igaku (2018), 73(11), 1504-1512.

WO 2019148089

WO 2019220369

Leukemia & Lymphoma (2020), 61(11), 2561-2567.

WO 2020097350

WO 2020086943

Journal of Immunotherapy (2020), 43(4), 107-120.

https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/breyanzi-lisocabtagene-maraleucel

CLIP

https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-lisocabtagene-maraleucel-relapsed-or-refractory-large-b-cell-lymphoma

On February 5, 2021, the Food and Drug Administration approved lisocabtagene maraleucel (Breyanzi, Juno Therapeutics, Inc.) for the treatment of adult patients with relapsed or refractory (R/R) large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.

Lisocabtagene maraleucel is a CD19-directed chimeric antigen receptor (CAR) T cell immunotherapy. It consists of autologous T cells that are genetically modified to produce a CAR protein, allowing the T cells to identify and eliminate CD19-expressing normal and malignant cells.

Efficacy was evaluated in TRANSCEND (NCT02631044), a single-arm, open label, multicenter trial that evaluated lisocabtagene maraleucel, preceded by lymphodepleting chemotherapy, in adults with R/R large B-cell lymphoma after at least two lines of therapy.

Of the 192 patients evaluable for response, the overall response rate (ORR) per independent review committee assessment was 73% (95% CI: 67, 80) with a complete response (CR) rate of 54% (95% CI: 47, 61). The median time to first response was one month. Of the 104 patients who achieved CR, 65% had remission lasting at least 6 months and 62% had remission lasting at least 9 months. The estimated median duration of response (DOR) was not reached (95% CI: 16.7 months, NR) in patients who achieved a CR. The estimated median DOR among patients with partial response was 1.4 months (95% CI: 1.1, 2.2).

Cytokine release syndrome (CRS) occurred in 46% of patients (Grade 3 or higher, 4%) and neurologic toxicity occurred in 35% (Grade 3 or higher, 12%). Three patients had fatal neurologic toxicity. Other Grade 3 or higher adverse reactions included infections (19%) and prolonged cytopenias (31%). FDA approved lisocabtagene maraleucel with a Risk Evaluation and Mitigation Strategy because of the risk of fatal or life-threatening CRS and neurologic toxicities.

The recommended regimen is a single dose containing 50 to 110 x 106 CAR-positive viable T cells with a 1:1 ratio of CD4 and CD8 components, administered by IV infusion and preceded by fludarabine and cyclophosphamide for lymphodepletion. Lisocabtagene maraleucel is not indicated for the treatment of patients with primary central nervous system lymphoma.

References

  1. Jump up to:a b c d “Lisocabtagene maraleucel”U.S. Food and Drug Administration (FDA). 5 February 2021. Retrieved 5 February 2021.  This article incorporates text from this source, which is in the public domain.
  2. ^ https://www.fda.gov/media/145711/download
  3. Jump up to:a b c d e f g h i j k l “FDA Approves New Treatment For Adults With Relapsed Or Refractory Large-B-Cell Lymphoma”U.S. Food and Drug Administration (FDA) (Press release). 5 February 2021. Retrieved 5 February 2021.  This article incorporates text from this source, which is in the public domain.

External links

Clinical data
Trade namesBreyanzi
Other namesJCAR017
License dataUS DailyMedLisocabtagene_maraleucel
Routes of
administration
Intravenous
ATC codeNone
Legal status
Legal statusUS: ℞-only [1][2]
Identifiers
UNII7K2YOJ14X0
KEGGD11990
ChEMBLChEMBL4297236

///////////Lisocabtagene maraleucel, BREYANZI, FDA 2021, APPROVALS 2021, リソカブタゲンマラルユーセル , Juno Therapeutics, JCAR 017, STN# BLA 125714

#Lisocabtagene maraleucel, #BREYANZI, #FDA 2021, #APPROVALS 2021, #リソカブタゲンマラルユーセル , #Juno Therapeutics, #JCAR 017, #STN# BLA 125714

Casimersen


Casimersen

カシメルセン;

RNA, [P-​deoxy-​P-​(dimethylamino)​]​(2′,​3′-​dideoxy-​2′,​3′-​imino-​2′,​3′-​seco)​(2’a→5′)​(C-​A-​A-​m5U-​G-​C-​C-​A-​m5U-​C-​C-​m5U-​G-​G-​A-​G-​m5U-​m5U-​C-​C-​m5U-​G)​, 5′-​[P-​[4-​[[2-​[2-​(2-​hydroxyethoxy)​ethoxy]​ethoxy]​carbonyl]​-​1-​piperazinyl]​-​N,​N-​dimethylphosphonamid​ate]

FormulaC268H424N124O95P22
CAS1422958-19-7
Mol weight7584.4307

FDA 2021/2/25 , Amondys 45, Antisense oligonucleotide
Treatment of Duchenne muscular dystrophy

Nucleic Acid Sequence

Sequence Length: 224 a 7 c 5 g 6 umodified

  • Exon-45: NG-12-0064
  • SRP-4045
  • WHO 10354

Casimersen, sold under the brand name Amondys 45, is an antisense oligonucleotide medication used for the treatment of Duchenne muscular dystrophy (DMD) in people who have a confirmed mutation of the dystrophin gene that is amenable to exon 45 skipping.[1][2][3][4] It is an antisense oligonucleotide of phosphorodiamidate morpholino oligomer (PMO).[1]

The most common side effects include upper respiratory tract infections, cough, fever, headache, joint pain and throat pain.[2]

Casimersen was approved for medical use in the United States in February 2021,[1][2] and it is the first FDA-approved targeted treatment for people who have a confirmed mutation of the DMD gene that is amenable to skipping exon 45.[2]

Duchenne muscular dystrophy (DMD) is an X-linked recessive allelic disorder characterized by a lack of functional dystrophin protein, which leads to progressive impairment of ambulatory, pulmonary, and cardiac function and is invariably fatal. A related, albeit a less severe, form of muscular dystrophy known as Becker muscular dystrophy (BMD) is characterized by shortened and partially functional dystrophin protein production. Although corticosteroids effectively slow disease progression in both DMD and BMD patients, they do not address the underlying molecular pathogenesis.1,2,3

The application of antisense oligonucleotides in DMD patients with specific mutations allows for exon skipping to produce truncated BMD-like dystrophin proteins, which restore partial muscle function and slow disease progression.1,2,4,5,7 Casimersen is a phosphorodiamidate morpholino oligonucleotide (PMO); PMOs are oligonucleotides in which the five-membered ribofuranosyl ring is replaced with a six-membered morpholino ring, and the phosphodiester links between nucleotides are replaced with a phosphorodiamidate linkage.6,7 In this manner, PMOs are much less susceptible to endo- and exonucleases and exhibit drastically reduced metabolic degradation compared to traditional synthetic oligonucleotides.6 Casimersen is the most recent in a line of approved PMOs for treating DMD, including eteplirsen and viltolarsen. However, the specific mutations, and hence the precise exon skipping, targeted by each is different.

Casimersen was granted accelerated FDA approval on February 25, 2021, based on data showing an increase in dystrophin levels in skeletal muscle of patients treated with casimersen; this approval is contingent on further verification in confirmatory trials. Casimersen is currently marketed under the tradename AMONDYS 45™ by Sarepta Therapeutics, Inc.7

Casimersen is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients confirmed to have a DMD gene mutation amenable to exon 45 skipping. This indication represents an accelerated approval based on observed efficacy; continued approval for this indication may be contingent on the verification of safety and efficacy in a confirmatory trial.7

Medical uses

Casimersen is indicated for the treatment of Duchenne muscular dystrophy (DMD) in people who have a confirmed mutation of the DMD gene that is amenable to exon 45 skipping.[1][2]

History

Casimersen was evaluated in a double-blind, placebo-controlled study in which 43 participants were randomized 2:1 to receive either intravenous casimersen or placebo.[2] All participants were male, between 7 and 20 years of age, and had a genetically confirmed mutation of the DMD gene that is amenable to exon 45 skipping.[2]

The U.S. Food and Drug Administration (FDA) granted the application for casimersen fast trackpriority review, and orphan drug designations.[2][5] The FDA granted the approval of Amondys 45 to Sarepta Therapeutics, Inc.[2]

Pharmacodynamics

Casimersen is an antisense phosphorodiamidate morpholino oligonucleotide designed to bind to exon 45 of the DMD pre-mRNA, preventing its inclusion in mature mRNA and allowing the production of an internally truncated dystrophin protein in patients who would normally produce no functional dystrophin. Due to the need for continuous alteration of mRNA splicing and its relatively short half-life, casimersen is administered weekly.7 Although casimersen is associated with mostly mild adverse effects, animal studies suggest a potential for nephrotoxicity, which has also been observed after administration of some oligonucleotides.4,7 Measurement of glomerular filtration rate before starting casimersen is advised. Serum cystatin C, urine dipstick, and urine protein-to-creatinine ratio should be measured before starting therapy. They should be measured monthly (urine dipstick) or every three months (serum cystatin C and urine protein-to-creatinine ratio) during treatment. Creatinine levels are not reliable in muscular dystrophy patients and should not be used. Any persistent alteration in kidney function should be further investigated.7

Mechanism of action

Duchenne muscular dystrophy (DMD) is an X-linked recessive allelic disorder that results in the absence of functional dystrophin, a large protein comprising an N-terminal actin-binding domain, C-terminal β-dystroglycan-binding domain, and 24 internal spectrin-like repeats.1,2,3 Dystrophin is vital for normal muscle function; the absence of dystrophin leads to muscle membrane damage, extracellular leakage of creatinine kinase, calcium influx, and gradual replacement of normal muscle tissue with fibrous and adipose tissue over time.1,2 DMD shows a characteristic disease progression with early functional complaints related to abnormal gait, locomotion, and falls that remain relatively stable until around seven years of age. The disease then progresses rapidly to loss of independent ambulatory function, ventilatory insufficiency, and cardiomyopathy, with death typically occurring in the second or third decade of life.1,2,3

The human DMD gene contains 79 exons spread over approximately 2.4 million nucleotides on the X chromosome.1 DMD is associated with a variety of underlying mutations, including exon duplications or deletions, as well as point mutations leading to nonsense translation through direct production of an in-frame stop codon, frameshift production of an in-frame stop codon, or aberrant inclusion of an intronic pseudo-exon with the concomitant production of an in-frame stop codon.1,2 In all cases, no functional dystrophin protein is produced. Becker muscular dystrophy (BMD) is a related condition with in-frame mutations that result in the production of a truncated but partially functional dystrophin protein. BMD patients, therefore, have milder symptoms, delayed disease progression, and longer life expectancy compared to DMD patients.1,2,3

Casimersen is an antisense phosphorodiamidate morpholino oligonucleotide designed to bind to exon 45 of the DMD pre-mRNA and prevent its inclusion within the mature mRNA before translation.4,7 It is estimated that around 8% of DMD patients may benefit from exon 45 skipping, in which the exclusion of this exon results in the production of an internally truncated and at least partly functional dystrophin protein.4,7,5 Although fibrotic or fatty muscle tissue developed previously cannot be improved, this therapy aims to slow further disease progression through the production of partially functional dystrophin and alleviation of the pathogenic mechanism of muscle tissue necrosis.1,2

TARGETACTIONSORGANISM
ADMD gene (exon 45 casimersen target site)binderHumans

Absorption

DMD patients receiving IV doses of 4-30 mg/kg/week revealed exposure in proportion to dose with no accumulation of casimersen in plasma with once-weekly dosing. Following a single IV dose, casimersen Cmax was reached by the end of infusion. Inter-subject variability, as measured by the coefficient of variation, ranged from 12-34% for Cmax and 16-34% for AUC.7

Pre-clinical studies in nonhuman primates (cynomolgus monkeys) investigated the pharmacokinetics of once-weekly casimersen administered at doses of 5, 40, and 320 mg/kg. On days 1 and 78, the 5 mg/kg dose resulted in a Cmax of 19.5 ± 3.43 and 21.6 ± 5.60 μg/mL and an AUC0-t of 24.9 ± 5.17 and 26.9 ± 7.94 μg*hr/mL. The 40 mg/kg dose resulted in a Cmax of 208 ± 35.2 and 242 ± 71.1 μg/mL and an AUC0-t of 283 ± 68.5 and 320 ± 111 μg*hr/mL. Lastly, the 320 mg/kg dose resulted in a a Cmax of 1470 ± 88.1 and 1490 ± 221 μg/mL and an AUC0-t of 1960 ± 243 and 1930 ± 382 μg*hr/mL.4

Volume of distribution

Casimersen administered at 30 mg/kg had a mean steady-state volume of distribution (%CV) of 367 mL/kg (28.9%).7

Protein binding

Casimersen binding to human plasma proteins is not concentration-dependent, ranging from 8.4-31.6%.7

Metabolism

Casimersen incubated with human hepatic microsomal preparations is metabolically stables and no metabolites are detected in plasma or urine.7

Route of elimination

Casimersen is predominantly (more than 90%) excreted in the urine unchanged with negligible fecal excretion.7

Half-life

Casimersen has an elimination half-life of 3.5 ± 0.4 hours.7

Clearance

Casimersen administered at 30 mg/kg has a plasma clearance of 180 mL/hr/kg.7

NAMEDOSAGESTRENGTHROUTELABELLERMARKETING STARTMARKETING END  
Amondys 45Injection50 mg/1mLIntravenousSarepta Therapeutics, Inc.2021-02-25Not applicableUS flag 

Synthesis Reference

Diane Elizabeth Frank and Richard K. Bestwick, “Exon skipping oligomers for muscular dystrophy.” U.S. Patent US20190262375A1, issued August 29, 2019.

PATENT

https://patents.google.com/patent/WO2017205879A2/en

also

WO 2021025899 

References

  1. Jump up to:a b c d e “Amondys 45- casimersen injection”DailyMed. Retrieved 1 March 2021.
  2. Jump up to:a b c d e f g h i j “FDA Approves Targeted Treatment for Rare Duchenne Muscular Dystrophy Mutation”U.S. Food and Drug Administration (FDA) (Press release). 25 February 2021. Retrieved 25 February 2021.  This article incorporates text from this source, which is in the public domain.
  3. ^ “Sarepta Therapeutics Announces FDA Approval of Amondys 45 (casimersen) Injection for the Treatment of Duchenne Muscular Dystrophy (DMD) in Patients Amenable to Skipping Exon 45” (Press release). Sarepta Therapeutics. 25 February 2021. Retrieved 25 February 2021 – via GlobeNewswire.
  4. ^ Rodrigues M, Yokota T (2018). “An Overview of Recent Advances and Clinical Applications of Exon Skipping and Splice Modulation for Muscular Dystrophy and Various Genetic Diseases”. Exon Skipping and Inclusion Therapies. Methods in Molecular Biology. 1828. Clifton, N.J. pp. 31–55. doi:10.1007/978-1-4939-8651-4_2ISBN 978-1-4939-8650-7PMID 30171533.
  5. ^ “Casimersen Orphan Drug Designations and Approvals”U.S. Food and Drug Administration (FDA). 4 June 2019. Retrieved 25 February 2021.

General References

  1. Wein N, Alfano L, Flanigan KM: Genetics and emerging treatments for Duchenne and Becker muscular dystrophy. Pediatr Clin North Am. 2015 Jun;62(3):723-42. doi: 10.1016/j.pcl.2015.03.008. Epub 2015 Apr 20. [PubMed:26022172]
  2. Verhaart IEC, Aartsma-Rus A: Therapeutic developments for Duchenne muscular dystrophy. Nat Rev Neurol. 2019 Jul;15(7):373-386. doi: 10.1038/s41582-019-0203-3. [PubMed:31147635]
  3. Mercuri E, Bonnemann CG, Muntoni F: Muscular dystrophies. Lancet. 2019 Nov 30;394(10213):2025-2038. doi: 10.1016/S0140-6736(19)32910-1. [PubMed:31789220]
  4. Carver MP, Charleston JS, Shanks C, Zhang J, Mense M, Sharma AK, Kaur H, Sazani P: Toxicological Characterization of Exon Skipping Phosphorodiamidate Morpholino Oligomers (PMOs) in Non-human Primates. J Neuromuscul Dis. 2016 Aug 30;3(3):381-393. doi: 10.3233/JND-160157. [PubMed:27854228]
  5. Rodrigues M, Yokota T: An Overview of Recent Advances and Clinical Applications of Exon Skipping and Splice Modulation for Muscular Dystrophy and Various Genetic Diseases. Methods Mol Biol. 2018;1828:31-55. doi: 10.1007/978-1-4939-8651-4_2. [PubMed:30171533]
  6. Smith CIE, Zain R: Therapeutic Oligonucleotides: State of the Art. Annu Rev Pharmacol Toxicol. 2019 Jan 6;59:605-630. doi: 10.1146/annurev-pharmtox-010818-021050. Epub 2018 Oct 9. [PubMed:30285540]
  7. FDA Approved Drug Products: AMONDYS 45 (casimersen) injection [Link]

External links

Clinical data
Trade namesAmondys 45
Other namesSRP-4045
License dataUS DailyMedCasimersen
Routes of
administration
Intravenous
Drug classAntisense oligonucleotide
ATC codeNone
Legal status
Legal statusUS: ℞-only [1][2]
Identifiers
CAS Number1422958-19-7
DrugBankDB14984
UNIIX8UHF7SX0R
KEGGD11988
Chemical and physical data
FormulaC268H424N124O95P22
Molar mass7584.536 g·mol−1

////////////Casimersen, FDA 2021, APPROVALS 2021, カシメルセン , Exon-45: NG-12-0064, SRP-4045, WHO 10354, Amondys 45, Antisense oligonucleotide, Duchenne muscular dystrophy

#Casimersen, #FDA 2021, #APPROVALS 2021, #カシメルセン , #Exon-45: NG-12-0064, #SRP-4045, #WHO 10354, #Amondys 45, #Antisense oligonucleotide, #Duchenne muscular dystrophy

Sequence:

1caaugccauc cuggaguucc ug

Sequence Modifications

TypeLocationDescription
modified basec-15′-ester
modified basec-1modified cytidine
modified basea-2modified adenosine
modified basea-3modified adenosine
modified baseu-4m5u
modified baseu-4modified uridine
modified baseg-5modified guanosine
modified basec-6modified cytidine
modified basec-7modified cytidine
modified basea-8modified adenosine
modified baseu-9modified uridine
modified baseu-9m5u
modified basec-10modified cytidine
modified basec-11modified cytidine
modified baseu-12m5u
modified baseu-12modified uridine
modified baseg-13modified guanosine
modified baseg-14modified guanosine
modified basea-15modified adenosine
modified baseg-16modified guanosine
modified baseu-17modified uridine
modified baseu-17m5u
modified baseu-18modified uridine
modified baseu-18m5u
modified basec-19modified cytidine
modified basec-20modified cytidine
modified baseu-21m5u
modified baseu-21modified uridine
modified baseg-22modified guanosine
uncommon linkc-1 – a-2unavailable
uncommon linka-2 – a-3unavailable
uncommon linka-3 – u-4unavailable
uncommon linku-4 – g-5unavailable
uncommon linkg-5 – c-6unavailable
uncommon linkc-6 – c-7unavailable
uncommon linkc-7 – a-8unavailable
uncommon linka-8 – u-9unavailable
uncommon linku-9 – c-10unavailable
uncommon linkc-10 – c-11unavailable
uncommon linkc-11 – u-12unavailable
uncommon linku-12 – g-13unavailable
uncommon linkg-13 – g-14unavailable
uncommon linkg-14 – a-15unavailable
uncommon linka-15 – g-16unavailable
uncommon linkg-16 – u-17unavailable
uncommon linku-17 – u-18unavailable
uncommon linku-18 – c-19unavailable
uncommon linkc-19 – c-20unavailable
uncommon linkc-20 – u-21unavailable
uncommon linku-21 – g-22unavailable
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